Systems, devices and methods for bilateral caloric vestibular stimulation

ABSTRACT

An in-ear stimulation device for administering caloric stimulation to the ear canal of a subject includes (a) first and second earpieces configured to be insertable into the ear canals of the subject; (b) at least first and second thermoelectric devices thermally coupled to respective ones of the first and second earpieces; (c) a first heat sink thermally coupled to the first thermoelectric device opposite the first earpiece and a second heat sink thermally coupled to the second thermoelectric device opposite the second earpiece; and (d) a controller comprising a waveform generator in communication with the first and second thermoelectric devices, the waveform generator configured to generate a first control signal to control a first caloric output to the first thermoelectric device and a second control signal to control a second caloric output to the second caloric device.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/994,266 filed on Jun. 14, 2013 which is a 35 US §371 national phaseentry of PCT Application No. PCT/US2011/065396, filed on Dec. 16, 2011and published in English on Jun. 21, 2012 as International PublicationNO. WO 2012/083126, which application claims priority to U.S.Provisional Patent Application No. 61/424,474, filed Dec. 17, 2010;61/498,131, filed Jun. 17, 2011; 61/497,761, filed Jun. 16, 2011;61/424,132, filed Dec. 17, 2010; 61/498,096, filed Jun. 17, 2011;61/424,326, filed Dec. 17, 2010; 61/498,080, filed Jun. 17, 2011;61/498,911, filed Jun. 20, 2011 and 61/498,943, filed Jun. 20, 2011; andU.S. patent application Ser. No. 12/970,312, filed Dec. 16, 2010 andSer. No. 12/970,347, filed Dec. 16, 2010 and PCT Application Nos.PCT/US2010/060764, filed Dec. 16, 2010, PCT/US2010/060771, filed Dec.16, 2010, the disclosure of each of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to caloric vestibular stimulation, and inparticular, to bilateral caloric vestibular stimulation.

BACKGROUND

Caloric vestibular stimulation (“CVS”) has long been known as adiagnostic procedure for testing the function of the vestibular system.In the traditional hospital setting, water caloric tests are used toassess levels of consciousness during acute or chronic brain injury. Thebrain injury may be due to head trauma or a central nervous system eventsuch as a stroke. Other brain injuries occur in the presence ofmetabolic abnormalities (e.g., kidney disease, diabetes), seizures, ortoxic levels of controlled substances or alcohol.

U.S. Patent Publication No. 2003/0195588 to Fischell et al. discusses astimulator in an ear canal that is adapted to provide magnetic,electrical, audible, tactile or caloric stimulation. Fischell proposes aring-shaped caloric transducer strip on an ear canal sensor/stimulatorsystem that may result in relatively slow thermal changes of the earcanal.

Accordingly, apparatuses and associated methods useful for deliveringstimulation to the nervous system and/or the vestibular system of anindividual that may be capable of relatively fast temperature changesare potentially beneficial to take full advantage of physiologicalresponses that are useful in diagnosing and/or treating a variety ofmedical conditions.

SUMMARY OF EMBODIMENTS OF THE INVENTION

In some embodiments, an in-ear stimulation device for administeringcaloric stimulation to the ear canal of a subject includes (a) first andsecond earpieces configured to be insertable into the ear canals of thesubject; (b) at least first and second thermoelectric devices thermallycoupled to respective ones of the first and second earpieces; (c) afirst heat sink thermally coupled to the first thermoelectric deviceopposite the first earpiece and a second heat sink thermally coupled tothe second thermoelectric device opposite the second earpiece; and (d) acontroller comprising a waveform generator in communication with thefirst and second thermoelectric devices, the waveform generatorconfigured to generate a first control signal to control a first caloricoutput to the first thermoelectric device and a second control signal tocontrol a second caloric output to the second caloric device.

In some embodiments, the first control signal is different from thesecond control signal.

In some embodiments, the first control signal is out-of-phase with thesecond control signal. When a slope of the first control signal isincreasing, a slope of the second control signal decreases, and when aslope of the first control signal is decreasing, a slope of the secondcontrol signal increases.

In some embodiments, the in-ear stimulation device comprises anelectrical connection between the first and second earpieces, and thecontroller comprises an impedance monitor configured to measure animpedance value between the first and second earpieces. The impedancemonitor may generate an estimate of a thermal contact of the first andsecond earpieces responsive to the impedance value. The impedancemonitor may estimate a poor thermal contact of the first and secondearpieces when the impedance value indicates an open circuit. Theimpedance monitor may be configured to determine whether the first andsecond earpieces were in position in the subject's ear canals duringadministration of the first and second control signals to therebydetermine a patient compliance with treatment protocol.

In some embodiments, the first and second heat sinks each comprise anouter portion positioned outside of the respective first and secondearpieces and an inner portion positioned inside respective earpieceinternal cavities. The first and second heat sink outer portions mayinclude a plurality of fins.

In some embodiments, the first and second heat sinks comprise aluminumand have a weight between about 30 grams and about 70 grams.

In some embodiments, the first and second earpieces are formed from arigid, thermally-conductive material.

In some embodiments, the first and second earpieces comprise aluminum.

In some embodiments, the first and second earpieces weigh about 9 gramsor less or about 4 grams or less.

In some embodiments, each of the first and second thermoelectric devicescomprise a first plurality of thermoelectric devices and a secondplurality of thermoelectric devices respectively. The first plurality ofthermoelectric devices may be thermally coupled to one another and thesecond plurality of thermoelectric devices may be thermally coupled toone another.

In some embodiments, the first and second thermoelectric devicescomprise a thin film thermoelectric device.

In some embodiments, the device includes a headpiece configured toposition the first earpiece in the right ear canal of the subject and toposition the second earpiece in the left ear canal of the subject.

In some embodiments, the first and second control signals are configuredsuch that the first and second caloric outputs are continuouslytemporally varying thermal waveforms and/or actively controlledwaveforms.

In some embodiments, the first and second control signals are configuredsuch that the first and second caloric outputs comprise at least oneperiod of a temporally varying thermal waveform, and at least one periodof stasis.

In some embodiments, the first caloric output cools one of the subject'sear canals and the second caloric output heats another of the subject'sear canals.

In some embodiments, the first and second caloric outputs are configuredto maintain a vestibular stimulation of the subject for at least fiveminutes.

In some embodiments, the vestibular stimulation for at least fiveminutes is sufficient to alter a vestibular phasic firing rate tothereby induce nystagmus over a period of at least five minutes. Thenystagmus may be sufficient to be detected using videonystagmographyand/or electronystagmography.

In some embodiments, the first and second earpieces, the first andsecond heat sinks, and the first and second thermoelectric devices areconfigured so that the first and second earpieces are cooled by therespective first and second thermoelectric devices at a rate of about15° C. per minute or more and heated by the respective first and secondthermoelectric devices at a rate of about 20° C. per minute or more.

In some embodiments, the device includes first and second fansconfigured to increase thermal dissipation from the first and secondheat sinks, respectively. The at least one fan may include at least twofans. In some embodiments, the at least one fan is configured to directair in a direction toward the heat sink.

In some embodiments, the device includes a securing member configured tosecure the first and second earpieces in the ear canal such that animpedance value between the first and second earpieces is substantiallyconstant.

In some embodiments, the securing member comprises a first ear enclosurehaving at least one adjustable bladder configured to increase in size tothereby decrease a pressure from the first earpiece in the ear canal,and to decrease in size to thereby increase a pressure from the firstearpiece in the ear canal.

In some embodiments, the first and second earpieces further comprise adistal end configured to be inserted in the ear canal and a proximal endconnected to the respective first and second thermal electric devices,and the first and second earpieces further comprise a insulating memberon the proximal end thereof. The insulating member may comprise siliconeand may be configured for positioning in the concha of the ear.

In some embodiments, the first and second earpieces include a pressurerelief channel that is sized and configured such that fluid flowsthrough the pressure relief channel during insertion of the earpieceinto the ear canal to thereby relieve pressure in the ear canal of thesubject during earpiece insertion.

In some embodiments, a first temperature sensor is coupled to the firstearpiece and a second temperature sensor is coupled to the secondearpiece. The controller may be in communication with the first andsecond temperature sensors and may be configured to receive temperatureinformation from the first and second temperature sensors. Thecontroller is configured to cease operation of the waveform generator ifthe temperature information indicates a temperature above or below apredefined temperature range.

In some embodiments, a first temperature sensor is coupled to the firstheat sink and a second temperature sensor is coupled to the second heatsink The controller may be in communication with the first and secondtemperature sensors and may be configured to receive temperatureinformation from the first and second temperature sensors, and thecontroller may be configured to cease operation of the waveformgenerator if the temperature information indicates a temperature aboveor below a predefined temperature range. The controller may beconfigured to store the temperature information and to analyze thetemperature information to determine a likelihood that the first andsecond earpieces are in thermal contact with the ear canals of thesubject during use.

In some embodiments, the controller comprises a voltage monitor thatdetects a voltage delivered by the waveform generator to the firstand/or second thermoelectric devices, and the controller may beconfigured to cease operation of the waveform generator if the voltageis greater than a predefined voltage threshold.

In some embodiments, a wired connection is between the controller andthe first and second thermoelectric devices, and the wired connection isconfigured to deliver the first and second control signals to the firstand second thermoelectric device. A first temperature sensor may becoupled to the first heat sink and a second temperature sensor coupledto the second heat sink. The first and second temperature sensors may beconfigured to transmit temperature information wirelessly. The first andsecond temperature sensors may be configured to transmit temperatureinformation wirelessly to the controller. In some embodiments, the firstand second temperature sensors may be configured to transmit temperatureinformation wirelessly to an external device.

In some embodiments, the first and second caloric outputs are activelycontrolled waveforms. The waveforms of the first and second caloricoutputs may be independently controlled based on one or more of thefollowing parameters: temperature amplitude, frequency, time varyingfrequency, a phasic relationship between the waveforms of the first andsecond caloric outputs, stochastic and/or structured noise modulation ofa temperature, frequency and/or phase of the waveforms of the first andsecond caloric outputs.

In some embodiments, methods for delivering caloric stimulation to asubject, the method include positioning at least a portion of an in-earstimulation device in the ear canals of the subject. The in-earstimulation device includes (a) first and second earpieces configured tobe insertable into the ear canals of the subject; (b) at least first andsecond thermoelectric devices thermally coupled to respective ones ofthe first and second earpieces; and (c) a first heat sink thermallycoupled to the first thermoelectric device opposite the first earpieceand a second heat sink thermally coupled to the second thermoelectricdevice opposite the second earpiece. The methods further includedelivering a first control signal to control a first caloric output tothe first thermoelectric device and a second control signal to control asecond caloric output to the second caloric device such that the firstand second thermoelectric devices effect corresponding temperaturechanges to the first and second earpieces, respectively, to delivercaloric stimulation to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of the specification, illustrate embodiments of the invention and,together with the description, serve to explain principles of theinvention.

FIG. 1 is a side view of a bilateral caloric vestibular stimulationdevice and controller according to some embodiments of the presentinvention;

FIG. 2 is an exploded view of the bilateral caloric vestibularstimulation device of FIG. 1;

FIG. 3 is a front and side view of a bilateral caloric vestibularstimulation device according to some embodiments of the presentinvention;

FIG. 4 is a side view of an earpiece with an inflatable cushionaccording to some embodiments of the present invention;

FIG. 5 is a side view of an earpiece with an insulative sleeve accordingto some embodiments of the present invention;

FIG. 6A is an exploded perspective view of an earpiece and heat sinkaccording to some embodiments of the present invention;

FIG. 6B is a side view of an earpiece and heat sink according to someembodiments of the present invention;

FIGS. 6C-6E are perspective, side and cross-sectional views,respectively, of an earpiece according to some embodiments of thepresent invention;

FIG. 7 is a schematic diagram of a bilateral caloric vestibularstimulation system according to some embodiments of the presentinvention;

FIG. 8 is a schematic diagram of the controller and earpieces of thebilateral thermal stimulation system of FIG. 7; and

FIGS. 9-20 are exemplary treatment waveforms that may be delivered usinga bilateral caloric vestibular stimulation device according toembodiments of the present invention.

FIG. 21 is a graph of nystagmus measured by electronystagmographyaccording to some embodiments of the present invention.

FIG. 22 is a graph of a 1/f weighted waveform over time according tosome embodiments of the present invention.

FIGS. 23A-F are schematic diagrams of various non-limiting examples ofwaveform stimuli that may be used to carry out the present invention.While each line A through E illustrates several cycles of a givenfrequency and waveform shape, note that “waveform” herein generallyrefers to a single cycle of a given frequency and waveform shape.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

The present invention now will be described hereinafter with referenceto the accompanying drawings and examples, in which embodiments of theinvention are shown. This invention may, however, be embodied in manydifferent forms and should not be construed as limited to theembodiments set forth herein. Rather, these embodiments are provided sothat this disclosure will be thorough and complete, and will fullyconvey the scope of the invention to those skilled in the art.

Like numbers refer to like elements throughout. In the figures, thethickness of certain lines, layers, components, elements or features maybe exaggerated for clarity.

DEFINITIONS

The terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention. Asused herein, the singular forms “a,” “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. It will be further understood that the terms “comprises”and/or “comprising,” when used in this specification, specify thepresence of stated features, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, steps, operations, elements, components, and/or groupsthereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items. As usedherein, phrases such as “between X and Y” and “between about X and Y”should be interpreted to include X and Y. As used herein, phrases suchas “between about X and Y” mean “between about X and about Y.” As usedherein, phrases such as “from about X to Y” mean “from about X to aboutY.”

Unless otherwise defined, all terms (including technical and scientificterms) used herein have the same meaning as commonly understood by oneof ordinary skill in the art to which this invention belongs. It will befurther understood that terms, such as those defined in commonly useddictionaries, should be interpreted as having a meaning that isconsistent with their meaning in the context of the specification andrelevant art and should not be interpreted in an idealized or overlyformal sense unless expressly so defined herein. Well-known functions orconstructions may not be described in detail for brevity and/or clarity.

It will be understood that when an element is referred to as being “on,”“attached” to, “connected” to, “coupled” with, “contacting,” etc.,another element, it can be directly on, attached to, connected to,coupled with or contacting the other element or intervening elements mayalso be present. In contrast, when an element is referred to as being,for example, “directly on,” “directly attached” to, “directly connected”to, “directly coupled” with or “directly contacting” another element,there are no intervening elements present. It will also be appreciatedby those of skill in the art that references to a structure or featurethat is disposed “adjacent” another feature may have portions thatoverlap or underlie the adjacent feature.

Spatially relative terms, such as “under,” “below,” “lower,” “over,”“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if the device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of “over” and “under.” The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly,” “downwardly,” “vertical,” “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

It will be understood that, although the terms “first,” “second,” etc.may be used herein to describe various elements, these elements shouldnot be limited by these terms. These terms are only used to distinguishone element from another. Thus, a “first” element discussed below couldalso be termed a “second” element without departing from the teachingsof the present invention. The sequence of operations (or steps) is notlimited to the order presented in the claims or figures unlessspecifically indicated otherwise.

The present invention is described below with reference to blockdiagrams and/or flowchart illustrations of methods, apparatus (systems)and/or computer program products according to embodiments of theinvention. It is understood that each block of the block diagrams and/orflowchart illustrations, and combinations of blocks in the blockdiagrams and/or flowchart illustrations, can be implemented by computerprogram instructions. These computer program instructions may beprovided to a processor of a general purpose computer, special purposecomputer, and/or other programmable data processing apparatus to producea machine, such that the instructions, which execute via the processorof the computer and/or other programmable data processing apparatus,create means for implementing the functions/acts specified in the blockdiagrams and/or flowchart block or blocks.

These computer program instructions may also be stored in acomputer-readable memory that can direct a computer or otherprogrammable data processing apparatus to function in a particularmanner, such that the instructions stored in the computer-readablememory produce an article of manufacture including instructions whichimplement the function/act specified in the block diagrams and/orflowchart block or blocks.

The computer program instructions may also be loaded onto a computer orother programmable data processing apparatus to cause a series ofoperational steps to be performed on the computer or other programmableapparatus to produce a computer-implemented process such that theinstructions which execute on the computer or other programmableapparatus provide steps for implementing the functions/acts specified inthe block diagrams and/or flowchart block or blocks.

Accordingly, the present invention may be embodied in hardware and/or insoftware (including firmware, resident software, micro-code, etc.).Furthermore, embodiments of the present invention may take the form of acomputer program product on a computer-usable or computer-readablenon-transient storage medium having computer-usable or computer-readableprogram code embodied in the medium for use by or in connection with aninstruction execution system.

The computer-usable or computer-readable medium may be, for example butnot limited to, an electronic, optical, electromagnetic, infrared, orsemiconductor system, apparatus, or device. More specific examples (anon-exhaustive list) of the computer-readable medium would include thefollowing: an electrical connection having one or more wires, a portablecomputer diskette, a random access memory (RAM), a read-only memory(ROM), an erasable programmable read-only memory (EPROM or Flash memorysuch as an SD card), an optical fiber, and a portable compact discread-only memory (CD-ROM).

As used herein, the term “vestibular system” has the meaning ascribed toit in the medical arts and includes but is not limited to those portionsof the inner ear known as the vestibular apparatus and thevestibulocochlear nerve. The vestibular system, therefore, furtherincludes, but is not limited to, those parts of the brain that processsignals from the vestibulocochlear nerve.

“Treatment,” “treat,” and “treating” refer to reversing, alleviating,reducing the severity of, delaying the onset of, inhibiting the progressof, or preventing a disease or disorder as described herein, or at leastone symptom of a disease or disorder as described herein (e.g., treatingone or more of tremors, bradykinesia, rigidity or postural instabilityassociated with Parkinson's disease; treating one or more of intrusivesymptoms (e.g., dissociative states, flashbacks, intrusive emotions,intrusive memories, nightmares, and night terrors), avoidant symptoms(e.g., avoiding emotions, avoiding relationships, avoidingresponsibility for others, avoiding situations reminiscent of thetraumatic event), hyperarousal symptoms (e.g., exaggerated startlereaction, explosive outbursts, extreme vigilance, irritability, panicsymptoms; sleep disturbance) associated with post-traumatic stressdisorder). In some embodiments, treatment may be administered after oneor more symptoms have developed. In other embodiments, treatment may beadministered in the absence of symptoms. For example, treatment may beadministered to a susceptible individual prior to the onset of symptoms(e.g., in light of a history of symptoms and/or in light of genetic orother susceptibility factors). Treatment may also be continued aftersymptoms have resolved—for example, to prevent or delay theirrecurrence. Treatment may comprise providing neuroprotection, enhancingcognition and/or increasing cognitive reserve. Treatment may be as anadjuvant treatment as further described herein.

“Adjuvant treatment” as described herein refers to a treatment sessionin which the delivery of one or more thermal waveforms to the vestibularsystem and/or the nervous system of a patient modifies the effect(s) ofone or more active agents and/or therapies. For example, the delivery ofone or more thermal waveforms to the vestibular system and/or thenervous system of a patient may enhance the effectiveness of apharmaceutical agent (by restoring the therapeutic efficacy of a drug towhich the patient had previously become habituated, for example).Likewise, the delivery of one or more thermal waveforms to thevestibular system and/or the nervous system of a patient may enhance theeffectiveness of counseling or psychotherapy. In some embodiments,delivery of one or more thermal waveforms to the vestibular systemand/or the nervous system of a patient may reduce or eliminate the needfor one or more active agents and/or therapies. Adjuvant treatments maybe effectuated by delivering one or more thermal waveforms to thevestibular system and/or the nervous system of a patient prior to,currently with and/or after administration of one or more active agentsand/or therapies.

“Chronic treatment,” “Chronically treating,” or the like refers to atherapeutic treatment carried out at least 2 to 3 times a week (or insome embodiments at least daily) over an extended period of time(typically at least one to two weeks, and in some embodiments at leastone to two months), for as long as required to achieve and/or maintaintherapeutic efficacy for the particular condition or disorder for whichthe treatment is carried out.

“Waveform” or “waveform stimulus” as used herein refers to the thermalstimulus (heating, cooling) delivered to the ear canal of a subjectthrough a suitable apparatus to carry out the methods described herein.“Waveform” is not to be confused with “frequency,” the latter termconcerning the rate of delivery of a particular waveform. The term“waveform” is used herein to refer to one complete cycle thereof, unlessadditional cycles (of the same, or different, waveform) are indicated.As discussed further below, time-varying waveforms may be preferred overconstant temperature applications in carrying out the present invention.

“Actively controlled waveform” or “actively controlled time-varyingwaveform” as used herein refers to a waveform stimulus in which theintensity of the stimulus or temperature of the earpiece delivering thatstimulus, is repeatedly adjusted, or substantially continuously adjustedor driven, throughout the treatment session, typically by controlcircuitry or a controller in response to active feedback from a suitablysituated temperature sensor (e.g., a temperature sensor mounted on theearpiece being driven by a thermoelectric device), so that drift of thethermal stimulus from that which is intended for delivery which wouldotherwise occur due to patient contact is minimized

In general, a waveform stimulus used to carry out the present inventioncomprises a leading edge, a peak, and a trailing edge. If a firstwaveform stimulus is followed by a second waveform stimulus, then theminimal stimulus point therebetween is referred to as a trough.

The first waveform of a treatment session is initiated at a start point,which start point may be the at or about the subject's body temperatureat the time the treatment session is initiated (typically a range ofabout 34 to 38 degrees Centigrade, around a normal body temperature ofabout 37 degrees Centigrade. The lower point, 34, is due to the coolnessof the ear canal. It typically will not be above about 37 unless thepatient is febrile). Note that, while the subject's ear canal may beslightly less than body temperature (e.g., about 34 to 36 degreesCentigrade), the starting temperature for the waveform is typically bodytemperature (the temp of the inner ear), or about 37 degrees Centigrade.In some embodiments, however, the temperature of the treatment devicemay not have equilibrated with the ear canal prior to the start of thetreatment session, and in such case the start point for at least thefirst waveform stimulus may be at a value closer to room temperature(about 23 to 26 degrees Centigrade).

The waveform leading edge is preferably ramped or time-varying: that is,the amplitude of the waveform increases through a plurality of differenttemperature points over time (e.g., at least 5, 10, or 15 or moredistinct temperature points, and in some embodiments at least 50, 100,or 150 or more distinct temperature points, from start to peak). Theshape of the leading edge may be a linear ramp, a curved ramp (e.g.,convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may be included in the waveform leading edge, solong as the remaining portion of the leading edge progresses through aplurality of different temperature points over time as noted above.

The peak of the waveform represents the amplitude of the waveform ascompared to the subject's body temperature. In general, an amplitude ofat least 5 or 7 degrees Centigrade is preferred for both heating andcooling waveform stimulation. In general, an amplitude of up to 20degrees Centigrade is preferred for cooling waveform stimulation. Ingeneral, an amplitude of up to 8 or 10 degrees Centigrade is preferredfor heating waveform stimulus. The peak of the waveform may be truncated(that is, the waveform may reach an extended temperature plateau), solong as the desired characteristics of the leading edge, and preferablytrailing edge, are retained. For heating waveforms, truncated peaks oflong duration (that is, maximum heat for a long duration) are lesspreferred, particularly at higher heats, due to potential burningsensation. In some embodiments, the temperature applied in the ear canalis between about 13° C. and 43° C. The temperature applied in the earcanal range from about 22-24° C. below body temperature to about 6-10°C. above body temperature.

The waveform trailing edge is preferably ramped or time-varying: thatis, the amplitude of the waveform decreases through a plurality ofdifferent temperature points over time (e.g., at least 5, 10, or 15 ormore distinct temperature points, or in some embodiments at least 50,100, or 150 or more distinct temperature points, from peak to trough).The shape of the trailing edge may be a linear ramp, a curved ramp(e.g., convex or concave; logarithmic or exponential), or a combinationthereof. A vertical cut may again be included in the waveform trailingedge, so long as the remaining portion of the trailing edge progressesthrough a plurality of different temperature points over time as notedabove.

The duration of the waveform stimulus (or the frequency of that waveformstimulus) is the time from the onset of the leading edge to either theconclusion of the trailing edge or (in the case of a vertically cutwaveform followed by a subsequent waveform). In general, each waveformstimulus has a duration, or frequency, of from one or two minutes up toten or twenty minutes.

A treatment session may have a total duration of five or ten minutes, upto 20 or 40 minutes or more, depending on factors such as the specificwaveform or waveforms delivered, the patient, the condition beingtreated, etc. For example, in some embodiments a treatment session maybe 60 minutes or more. In some embodiments, treatment sessions mayinclude breaks between stimulation, such as breaks of a minute or more.

In a treatment session, a plurality of waveforms may be delivered insequence. In general, a treatment session will comprise 1, 2 or 3waveforms, up to about 10 or 20 or more waveforms deliveredsequentially. Each individual waveform may be the same, or different,from the other. When a waveform is followed by a subsequent waveform,the minimum stimulus point (minimum heating or cooling) between isreferred to as the trough. Like a peak, the trough may be truncated, solong as the desired characteristics of the trailing edge, and thefollowing next leading edge, are retained. While the trough mayrepresent a return to the subject's current body temperature, in someembodiments minor thermal stimulation (cooling or heating; e.g, by 1 or2 degrees up to 4 or 5 degrees Centigrade) may continue to be applied atthe trough (or through a truncated trough).

Treatment sessions are preferably once a day, though in some embodimentsmore frequent treatment sessions (e.g. two or three times a day) may beemployed. Day-to-day treatments may be by any suitable schedule: everyday; every other day; twice a week; as needed by the subject, etc. Theoverall pattern of treatment is thus typically chronic (in contrast to“acute,” as used in one-time experimental studies).

Subjects may be treated with the present invention for any reason. Insome embodiments, disorders for which treatment may be carried outinclude, include, but are not limited to, migraine headaches (acute andchronic), depression, anxiety (e.g. as experienced in post-traumaticstress disorder (“PTSD”) or other anxiety disorders), spatial neglect,Parkinson's disease, seizures (e.g., epileptic seizures), diabetes(e.g., type II diabetes), etc.

Headaches that may be treated by the methods and apparatuses of thepresent invention include, but are not limited to, primary headaches(e.g., migraine headaches, tension-type headaches, trigeminal autonomiccephalagias and other primary headaches, such as cough headaches andexertional headaches) and secondary headaches. See, e.g., InternationalHeadache Society Classification ICHD-II.

Migraine headaches that may be treated by the methods and apparatuses ofthe present invention may be acute/chronic and unilateral/bilateral. Themigraine headache may be of any type, including, but not limited to,migraine with aura, migraine without aura, hemiplegic migraine,opthalmoplegic migraine, retinal migraine, basilar artery migraine,abdominal migraine, vestibular migraine and probable migraine. As usedherein, the term “vesibular migraine” refers to migraine with associatedvestibular symptoms, including, but not limited to, head motionintolerance, unsteadiness, dizziness and vertigo. Vestibular migraineincludes, but is not limited to, those conditions sometimes referred toas vertigo with migraine, migraine-associated dizziness,migraine-related vestibulopathy, migrainous vertigo and migraine-relatedvertigo. See, e.g., Teggi et al., HEADACHE 49:435-444 (2009).

Tension-type headaches that may be treated by the methods andapparatuses of the present invention, include, but are not limited to,infrequent episodic tension-type headaches, frequent episodictension-type headaches, chronic tension-type headache and probabletension-type headache.

Trigeminal autonomic cephalagias that may be treated by the methods andapparatuses of the present invention, include, but are not limited to,cluster headaches, paroxysmal hemicranias, short-lasting unilateralneuralgiform headache attacks with conjunctival injection and tearingand probable trigeminal autonomic cephalagias. Cluster headache,sometimes referred to as “suicide headache,” is considered differentfrom migraine headache. Cluster headache is a neurological disease thatinvolves, as its most prominent feature, an immense degree of pain.“Cluster” refers to the tendency of these headaches to occurperiodically, with active periods interrupted by spontaneous remissions.The cause of the disease is currently unknown. Cluster headaches affectapproximately 0.1% of the population, and men are more commonly affectedthan women (in contrast to migraine headache, where women are morecommonly affected than men).

Other primary headaches that may be treated by the methods andapparatuses of the present invention, include, but are not limited to,primary cough headache, primary exertional headache, primary headacheassociated with sexual activity, hypnic headache, primary thunderclapheadache, hemicranias continua and new daily-persistent headache.

Additional disorders and conditions that can be treated by the methodsand systems of the present invention include, but are not limited to,neuropathic pain (e.g., migraine headaches), tinnitus, brain injury(acute brain injury, excitotoxic brain injury, traumatic brain injury,etc.), spinal cord injury, body image or integrity disorders (e.g.,spatial neglect), visual intrusive imagery, neuropsychiatric disorders(e.g. depression), bipolar disorder, neurodegenerative disorders (e.g.Parkinson's disease), asthma, dementia, insomnia, stroke, cellularischemia, metabolic disorders, (e.g., diabetes), post-traumatic stressdisorder (“PTSD”), addictive disorders, sensory disorders, motordisorders, and cognitive disorders.

Sensory disorders that may be treated by the methods and apparatuses ofthe present invention include, but are not limited to, vertigo,dizziness, seasickness, travel sickness cybersickness, sensoryprocessing disorder, hyperacusis, fibromyalgia, neuropathic pain(including, but not limited to, complex regional pain syndrome, phantomlimb pain, thalamic pain syndrome, craniofacial pain, cranialneuropathy, autonomic neuropathy, and peripheral neuropathy (including,but not limited to, entrapment-, heredity-, acute inflammatory-,diabetes-, alcoholism-, industrial toxin-, Leprosy-, Epstein BarrVirus-, liver disease-, ischemia-, and drug-induced neuropathy)),numbness, hemianesthesia, and nerve/root plexus disorders (including,but not limited to, traumatic radiculopathies, neoplasticradiculopathies, vaculitis, and radiation plexopathy).

Motor disorders that may be treated by the method and apparatuses of thepresent invention include, but are not limited to, upper motor neurondisorders such as spastic paraplegia, lower motor neuron disorders suchas spinal muscular atrophy and bulbar palsy, combined upper and lowermotor neuron syndromes such as familial amyotrophic lateral sclerosisand primary lateral sclerosis, and movement disorders (including, butnot limited to, Parkinson's disease, tremor, dystonia, TouretteSyndrome, myoclonus, chorea, nystagmus, spasticity, agraphia,dysgraphia, alien limb syndrome, and drug-induced movement disorders).

Cognitive disorders that may be treated by the method and apparatuses ofthe present invention include, but are not limited to, schizophrenia,addiction, anxiety disorders, depression, bipolar disorder, dementia,insomnia, narcolepsy, autism, Alzheimer's disease, anomia, aphasia,dysphasia, parosmia, spatial neglect, attention deficit hyperactivitydisorder, obsessive compulsive disorder, eating disorders, body imagedisorders, body integrity disorders, post-traumatic stress disorder,intrusive imagery disorders, and mutism.

Metabolic disorders that may be treated by the present invention includediabetes (particularly type II diabetes), hypertension, obesity, etc.

Addiction, addictive disorders, or addictive behavior that may betreated by the present invention includes, but is not limited to,alcohol addiction, tobacco or nicotine addiction (e.g., using thepresent invention as a smoking cessation aid), drug addictions (e.g.,opiates, oxycontin, amphetamines, etc.), food addictions (compulsiveeating disorders), etc.

In some embodiments, the subject has two or more of the aboveconditions, and both conditions are treated concurrently with themethods and systems of the invention. For example, a subject with bothdepression and anxiety (e.g., PTSD) can be treated for both,concurrently, with the methods and systems of the present invention.

The methods and systems according to embodiments of the presentinvention utilize thermoelectric devices (TEDs) to induce physiologicaland/or psychological responses in a subject for medically diagnosticand/or therapeutic purposes. Subjects to be treated and/or stimulatedwith the methods, devices and systems of the present invention includeboth human subjects and animal subjects. In particular, embodiments ofthe present invention may be used to diagnose and/or treat mammaliansubjects such as cats, dogs, monkeys, etc. for medical research orveterinary purposes.

As noted above, embodiments according to the present invention utilizeTEDs to provide an in-ear stimulator for administering thermalstimulation in the ear canal of the subject. The ear canal serves as auseful conduit to the individual's vestibular system and to thevestibulocochlear nerve. Without wishing to be bound by any particulartheory, it is believed that thermal stimulation of the vestibular systemis translated into electrical stimulation within the central nervoussystem (“CNS”) and propagated throughout the brain, including but notlimited to the brain stem, resulting in certain physiological changesthat may be useful in treating various disease states (increased bloodflow, generation of neurotransmitters, etc). See, e.g., Zhang, et al.Chinese Medical J. 121:12:1120 (2008) (demonstrating increased ascorbicacid concentration in response to cold water CVS).

System

As illustrated in FIGS. 1-2, an in-ear stimulation apparatus 10 includesa support or headband 12, earphones 14 and a controller and/or powerconnection or cable 16. The earphones 14 include respective earpieces100 that are configured to be positioned in the ear of a patient orsubject. As illustrated in FIG. 2, the earphones 14 include a cushion 20connected a housing 22 having housing members 24 and 26, the earpiece100, a thermoelectric (TED) device 30, a temperature sensor 40, a heatsink 50 with a heat sink spacer 52 and a heat sink base 54 with heatdissipating fins 56 and apertures 58, and two air flow devices or fans60 and 62. The housing 22 includes ventilation apertures 27 forincreasing air flow, e.g., via the fans 60, 62 for increasingdissipation of thermal energy. The housing 22 also includes cableapertures 28 for holding electrical connections to the cable 16 such asa power and/or communication cable that controls operations of the fans60, 62, the TED 30, and/or the temperature sensor 40. The electricalconnections (not shown) may further pass through the apertures 58 in theheat sink base to connect with the TED 30 and/or temperature sensor 40.

As illustrated, the temperature sensor 40 may be inserted into a cavityor void in the earpiece 100. However, the temperature sensor 40 may bepositioned in any suitable position to sense a temperature of theearpiece 100. As shown in FIG. 6E, the temperature sensor 40 may beinserted into a cavity 102.

The TED 30 is thermally coupled between the earpiece 100 and the heatsink 50 as illustrated in FIG. 2. Although the device 10 is illustratedwith one TED 30 in FIG. 2, it should be understood that, in someembodiments, two or more TEDs may be used. In some embodiments, the TEDsare impregnated with and/or connect to the earpiece 100 and heat sink 50with epoxy to increase a thermal conductivity between the TEDs, theearpiece 100 and/or the heat sink 50. Thus, the TEDs between theearpiece 100 and the heat sink 50 create a temperature differencebetween the earpiece 100 and the heat sink 50 when a voltage is appliedto the TEDs so that the temperature of the earpiece 100 may be increaseand/or decreased. The TEDs may be controlled by a controller 200, andthe efficiency with which the temperature of the earpiece 100 is changedmay be increased by the heat sink 50, which dissipates excess heat orcold from the side of the TEDs opposite the earpiece 100 into thesurrounding environment. The heat sink 50 may be passively cooled oractively cooled, for example, by using a fan or other cooling system tofurther increase heat dissipation. As discussed above, the ear canal mayserve as a useful conduit to the subject's vestibular system and/or tothe vestibulocochlear nerve for thermal stimulation for providingcaloric vestibular stimulation (CVS) and/or cranial nerve stimulation.In some embodiments, commercially available heat sinks may be used, suchas from Wakefield Thermal Solutions, Inc., Pelham, N.H., U.S.A. (e.g.,Part Number: 609-50AB).

In some embodiments, the slew rate for the earpieces 100 is about 15°C./minute or greater for cooling the earpiece 100 and 20° C./minute orgreater for heating the earpiece 100. Heating the earpiece may be fasterand more efficient than cooling.

Thin film TEDs, Peltier coolers/heaters or transducers may be used astransducers in some embodiments, including, but not limited to, the thinfilm TEDs described in U.S. Pat. No. 6,300,150 and U.S. PatentPublication Nos. 2007/0028956 and 2006/0086118; however, any suitableTED, such as semiconductor diode TED's, may be used. Such TEDs may alsoincorporate a temperature sensing function, so that temperature sensingcan be accomplished through the same device without the need for aseparate temperature sensor. In some embodiments, the temperature sensor40 may be a thermistor or other temperature sensing element that isdisposed in the distal end of the earpiece and used as a feedback sensorto allow the controller 200 to maintain the proper temperature for agiven thermal waveform. TEDs are commercially available from TETechnology, Inc, (Traverse City, Mich., USA), Nextreme ThermalSolultions (Durham, N.C., USA)(e.g., OptoCooler™ Series (UPT40 andUPF4), Eteg™ UPF40) and Micropelt, GmbH (Freiburg, Germany)(e.g.,MPC-D303 and MPC-D305). Although embodiments according to the inventionare described herein with respect to TEDs, it should be understood thatany suitable type of thermal device may be used, including opticalheating (e.g., using a laser) and ultrasound heating (e.g., apiezoelectric heating device). TEDs may be provided that include a heatflux of 80-120 W/cm² or more. The TEDs may be generally rectangular inshape, with typical rectangular areas being about 2×1 mm or 5×2 mm ormore and having a height profile of 1 mm or 0.65 mm or 0.5 mm or less.In particular embodiments, the TED is about a rectangular shape havingsides of about 12-13 mm and a heigh profile of about 3 mm. When morethan one TED is used, the TEDs may be connected in parallel or in seriesto provide thermal changes to a desired region of an earpiece and/orheat sink.

In some embodiments, the cushion 20 and/or heat sink spacer 52 may besized and/or configured to increase comfort and/or the fit of theearpiece 100 in the subject's ear canal. The cushion 20 and/or spacer 52may be sized or may be adjustable so as to place the earpiece 100 in theear canal with sufficient thermal contact, but without placing excessivepressure on the ear canal. In some embodiments, the controller 200controls operation of the TED 30 via additional electricalconnections/controllers, such as a PCB (not shown), which may beelectrically connected to the TED 30 either via cables or between theearpiece 100 and the heat sink 50 and may provide a power supply andcontrol signals for operating the TEDs, such as control signals tocontrol desired temperatures and temperature changes, from thecontroller. The controller 200 receives feedback from the temperaturesensor 40 in the distal end of the earpiece that may properly modulatethe power applied to the TED so as to generate the desired thermalwaveform. In addition, the cable 16 may include an electrical connectionbetween the two earpieces 100 that may be used to provide an impedancemeasurement to estimate a degree of electrical and thermal contactbetween the earpieces. The earpiece 100 may further include atemperature sensor/controller so that the TEDs may provide a temperaturestability, e.g., of about 0.1-0.5° C.

It should be understood that other configurations for supporting theheadphones and/or earpieces may be used, including support bands thatare positioned under the chin or over the ear, for example, as may beused with audio earphones. For example, FIG. 3 illustrates four strapsor headbands 12′ and earphones 14′. The headbands 12′ may provideincreased stability of the earphones 14′ to provide potentially improvedthermal contact of the earpieces (not shown).

Additional configurations may be used to potentially increase comfortand/or fit of the headset and/or improve a thermal contact between theearpiece 100 and the ear canal. For example, as shown in FIG. 4, thecushion 20 can include an inlet 21 for inflating an inner chamber of thecushion 20. In this configuration, the distance of the earpiece 100 fromthe subject's head may be controlled by adjusting an amount of fluid,such as air, that is added into or released from the cushion 20. As thecushion 20 inflates, the earpiece 100 is pushed further away from thesubject's head, and when the cushion 20 is deflated, the earpiece 100may be pressed closer to the subject's head for a tighter fit betweenthe earpiece 100 and the ear canal.

Earpiece

In some embodiments as shown in FIG. 5, a sheath 101 may be provided toinsulate the base portion of the earpiece 100. Without wishing to bebound by theory, is currently believed that changes in temperature ofthe earpiece should be concentrated at a part of the earpiece 100 thatis inserted the deepest into the ear canal for increasing caloricvestibular stimulation. Accordingly, the sheath 101 may reduce a thermalcoupling of the base of the earpiece 100 with the subject's ear toprovide more efficient heating and cooling to the distal end of theearpiece 100. In addition, the sheath 101 in some embodiments mayprovide additional cushioning or padding for increased comfort to theuser. The sheath 101 may be formed of any suitable material, such aselastomer or polymeric material, medical grade silicone and the like.Moreover, in some embodiments, the earpiece 100 may be covered with athermally conductive material to increase a thermal contact with the earcanal. In some embodiments, a thermally conductive material may beapplied only to the distal end of the earpiece 100; however, any portionof the earpiece 100 may incorporate thermally conductive materials. Anysuitable thermally conductive material may be used, including gels,water, water-based lubricants, and the like. In some embodiments, thethermally conductive material is a coating material that is applied andreapplied to the earpiece 100 before each use. In some embodiments, thethermally conductive material may be a sheath or sleeve (e.g., a gel orplastic sleeve) that is fitted to the earpiece during use and may bereusable. Therefore, it should be understood that coatings or sheathmaterials may be provided to selectively thermally insulate the earpiece100 or to increase a thermal conductivity between the earpiece 100 andthe ear canal.

In some embodiments, the sheath 101 may be a layer (e.g., around 1 mm)that is selectively applied to the base of the earpiece 100 but not thedistal tip portion that is inserted into the ear canal. In addition tothermally insulating the base of the earpiece 100, the sheath 101 mayalso provide a cushion against the inward pressure of the headset, thusenhancing patient comfort during the CVS therapy application. The sheath101 may also be electrically insulating as well as thermally insulating.

As shown in FIG. 6A, the earpiece 100 may be connected to the heat sink50 by the TED 30. The heat sink 50 is thermally isolated from theearpiece 100. The TEDs 30 are positioned on a surface 53 of a spacerportion 52 of the heat sink 50 so that thermal coupling between the TED30 and the earpiece 100 may be achieved. The TEDs 30 are also thermallycoupled to the heat sink 50 on a side of the TEDs that are opposite tothe earpiece 100 so as to create a thermal differential between the heatsink 50 and the earpiece 100. The TED 30 may be adhered to the earpiece100 using a thermally conductive adhesive, such as silver. It should beunderstood that the TED 30 may be thermally connected to the earpiece100 and heat sink 50 at any suitable location to provide a thermaldifferential between the heat sink 50 and the earpiece 100.

In some embodiments, the earpiece 100 may be connected to an electricalconnection or electrode 45. Although the electrode 45 is illustrated onan outer surface of the earpiece 100, it should be understood that theelectrode 45 may be connected to interior surfaces or embedded in theearpiece in any configuration that is suitable to electrically connectthe electrode 45 with the earpiece. In this configuration, a relativelysmall electrical current may be applied via the electrode 45 to bothearpieces 100 shown, e.g., in FIG. 1. Without wishing to be bound bytheory, it is believed that if generally good thermal contact betweenthe earpiece 100 and the ear canal is achieved, then the patient'sbody/head will generally complete an electrical circuit between theearpieces 100. Thus, the impedance or other equivalent electricalmeasurement between the earpieces 100 may be measured to estimate athermal contact between the earpieces 100 and the ear canal of thepatient and/or to measure patient compliance with treatment.

As shown in FIG. 6B, the TEDs 30 may be disposed between the base of theearpiece 100 and the heat sink 50 and impregnated with epoxy 32. In someembodiments, the epoxy 32 provides structural stability to the earpiece100, TED 30 and heat sink 50 assembly. However, it should be understoodthat any suitable configuration may be used, and in some embodiments,the epoxy may be omitted and/or thermally conductive adhesives may beused. Additional configurations of heat sinks, TEDs and earpieces thatmay be used in some embodiments of the present invention are discussedin U.S. patent application Ser. Nos. 12/970,347 and 12/970,312, filedDec. 16, 2010, the disclosures of which are hereby incorporated byreference in their entireties. In this configuration, caloric vestibularstimulation may be administered to a subject via the subject's earcanal.

As shown in FIGS. 6C-6E, the earpiece 100 includes a tip cavity 102, abase cavity 104, base apertures 106, and an pressure relief channel 110.The tip cavity 102 is configured to receive a thermistor or temperaturesensor, such as the temperature sensor 40 so that the temperature of thetip of the earpiece 100 may be monitored. The base cavity 104 isconfigured to receive the TED 30 such that the TED 30 is mounted on aninterior cavity surface of the earpiece 100 on one side, and the TED 30is mounted on the heat sink 50 on the opposite side as described in FIG.2. The base apertures 106 are configured to provide a passageway forwires and/or cables to connect a power source and/or control signal tothe TED 30 and/or temperature sensor 40 or other sensors and/or monitorsthat may be used with the earpiece 100.

The pressure relief channel 110 is configured to provide a pathwaythrough which air may flow during and/or after insertion of the earpiece100 into the ear canal of the patient. Accordingly, the earpiece 100 maybe formed of a rigid material, e.g., a metal such as aluminum that hasan associated specific heat such that the earpiece may provide a slewrate that is about 15° C./minute or greater for cooling the earpiece 100and 20° C./minute or greater for heating the earpiece 100. However, therigid surface of the earpiece 100 may result in a increased pressureduring insertion because the generally non-conformable surface of theearpiece 100 may seal air inside the ear canal. Thus, the pressurerelief channel 110 may permit additional airflow through the channel 110to reduce the pressure in the ear canal during and/or after theinsertion of the earpiece 100 into the ear canal of the patient. In thisconfiguration, the earpiece comfort and/or fit may be improved toprovide a close thermal contact between the generally rigid surface ofthe earpiece 100 and the ear canal of the patient to increase theefficiency with which the vestibular nerve may be thermally stimulated.The pressure relief channel 110 may be of a length and depth that issufficient to provide air flow from the interior of the ear canal at thedistal tip of the earpiece to the external air outside of the ear canal.For example, the channel 110 may be generally as long as a side of theearpiece 100 and may be between about 0.5 mm and about 2.0 mm deep.

Although the pressure relief channel 110 is illustrated as being on aside of the earpiece 100 that extends nearly vertically away from thebase, it should be understood that the pressure relief channel 110 maybe positioned on any portion of the outer surface of the earpiece 100.Moreover, in some embodiments, a pressure relief channel may bepositioned on an interior portion of the earpiece 100 to provide aconduit between the interior ear canal of the patient and the exteriorair.

In some embodiments, the earpiece 100 may be coated to preventdegradation of the surface quality. Depending on the application, thecoating may be electrically conductive, electrically non-conductive, ora combination of both. For example, the surface of the earpiece 100 maybe anodized such that a non-conductive coating is grown on aluminumusing an anodization process. This process creates an aluminum oxidecoating that renders the surface electrically insulting. The coating isvery thin, however, and there is little if any degradation of thethermal conductivity. Colorants may be added during the anodization fora visually enhanced appearance. The aluminum may also be coated with anelectrically conductive material, which can be applied by painting,dipping, spraying, etc. Such a coating may also prevent surfacedegradation by keeping the underlying aluminum from being exposed toair. The layer can be applied so as to have a minimal change or nochange in the degradation of thermal conductivity. In particularembodiments, the earpiece 100 may be patterned with more than onecoating, using techniques common in the art, so that both electricallyconductive and non-conductive coatings may coexist on the earpiece.

In some embodiments, impedance may be measured using the electrode 45 inFIG. 6A. Impedance is a complex quantity (that is, having both real andimaginary parts) that may combine both resistive (real) and capacitive(imaginary) components, and impedance may be measured with analternating current/voltage method. The capacitance may be measured withelectrically insulated earpieces (e.g., anodized), but electricallyinsulated earpieces would generally not permit a measurement ofresistance, which would typically require electrical contact between theearpiece 100 and the ear canal. The earpiece 100 may be patterned withelectrically insulating and electrically conductive portions so that thebase is anodized and the distal tip has a conductive coating. This wouldallow both resistance and capacitance to be measured (or the entireearpiece could be coated with an electrically conductive material). Insummary, either coating type could be used to measure an impedance valuefor estimating a thermal conductivity.

Although embodiments according to the present invention are describedherein with respect to a device with two earpieces (see, e.g., theearpieces 100A, 100B in FIG. 8), it should be understood that in someembodiments, a single earpiece may be used to deliver thermal vestibularstimulation to one ear canal of a patient. A single earpiece caloricvestibular stimulation device may utilize a single earpiece havingvarious combinations of the features described herein.

Controllers

FIG. 7 is a block diagram of exemplary embodiments of controller systems200 of the present invention for controlling a thermal output to twoearpieces 100A, 100B to administer various thermal treatment protocolsor thermal “prescriptions.” As shown in FIG. 7, in some embodiments, thecontroller 200 includes a memory 236, a processor 225 and I/O circuits246 and is operatively and communicatively coupled to the earpieces100A, 100B. The processor 225 communicates with the memory 236 via anaddress/data bus 248 and with the I/O circuits via an address/data bus249. As will be appreciated by one of skill in the art, the processor225 may be any commercially available or custom microprocessor. Thememory 236 is representative of the overall hierarchy of memory devicescontaining software and data used to implement the functionality of thecontroller 200. Memory 236 may include, but is not limited to, thefollowing types of devices: cache, ROM, PROM, EPROM, EEPROM, flashmemory, SRAM and DRAM.

As shown in FIG. 7, the controller memory 236 may comprise severalcategories of software and data: an operating system 252, applications254, data 256 and input/output (I/O) device drivers 258.

As will be appreciated by one of skill in the art, the controller mayuse any suitable operating system 252, including, but not limited to,OS/2, AIX, OS/390 or System390 from International Business MachinesCorp. (Armonk, N.Y.), Window CE, Windows NT, Windows2003, Windows2007 orWindows Vista from Microsoft Corp. (Redmond, Wash.), Mac OS from Apple,Inc. (Cupertino, Calif.), Unix, Linux or Android.

The applications 254 may include one or more programs configured toimplement one or more of the various operations and features accordingto embodiments of the present invention. The applications 254 mayinclude a thermal waveform control module 220 configured to communicatea waveform control signal to one or both of the TED's of the earpieces100A, 100B. The applications 254 may also include an impedance module222 for measuring an impedance or other analogous electricalcharacteristic (e.g., capacitance) between the earpieces 100A, 100B, apatient module 223 for monitoring patient-specific data, such ascompliance and/or a safety monitoring module 227. In some embodiments,the memory 236 comprises additional applications, such as a networkingmodule for connecting to a network, for example, as discussed in U.S.Provisional Application Ser. No. 61/424,474 filed Dec. 17, 2010, thedisclosure of which is incorporated by reference in its entirety. Insome embodiments, the waveform module 220 may be configured to activateat least one TED (i.e., to control the magnitude, duration, waveform andother attributes of stimulation delivered by the at least one TED). Insome such embodiments, the control module 220 is configured to activateat least one TED based upon a prescription from a prescription database,which may include one or more sets of instructions for delivering one ormore time-varying thermal waveforms to the vestibular system of asubject as described in U.S. Provisional Application Ser. No. 61/424,474filed Dec. 17, 2010. In some such embodiments, the waveform module 220is configured to selectively and separately activate a plurality of TEDs(e.g., by activating only one of the plurality of TEDs, by heating oneTED and cooling another, by sequentially activating the TEDs, byactivating different TEDs using different temperature/timing parameters,combinations of some or all of the foregoing, etc.).

The data 256 may comprise static and/or dynamic data used by theoperating system 252, applications 254, I/O device drivers 258 and othersoftware components. The data 256 may include a thermal waveformdatabase 226 including one or more thermal treatment protocols orprescriptions. In some embodiments, the data 256 further includesimpedance data 224 including impedance measurements between theearpieces and/or estimates of thermal contact based on electricalimpedance measurements. Electrical impedance measurements may includeresistive and capacitive components, which may be correlated with athermal impedance or thermal conductance of the interface between theearpieces 100A, 100B and the ear canal. In some embodiments, the memory236 includes additional data, such as data associated with the deliveryof one or more time-varying thermal waveforms, including patientoutcomes, temperature measurements of the ear as a result of the thermalstimulation, and the like.

I/O device drivers 258 typically comprise software routines accessedthrough the operating system 252 by the applications 254 to communicatewith devices such as I/O ports, memory 236 components and/or the TEDdevice 30.

In some embodiments, the TED thermal waveform control module 220 isconfigured to activate at least one TED in the earpieces 100A, 100B tostimulate the nervous system and/or the vestibular system of a subject.In particular embodiments, the TED thermal control waveform module 220is configured to activate at least one TED based upon a thermalprescription comprising a set of instructions for delivering one or moretime-varying thermal waveforms to the vestibular system of a subject.

In some embodiments, the controller 200 is communicatively connected toat least one TED in the earpiece 100 via a thermal stimulationconductive line. In some embodiments, the controller 200 is operativelyconnected to a plurality of TEDs, and the controller 200 may beoperatively connected to each TED via a separate thermal stimulationconductive line. In some such embodiments, each of the plurality ofseparate thermal stimulation conductive lines is bundled together intoone or more leads (e.g., the thermal stimulation conductive linesconnected to the TED(s) thermally coupled to the right earpiece may bebundled separately from the thermal stimulation conductive linesconnected to the TED(s) thermally coupled to the left earpiece). In somesuch embodiments, the thermal stimulation conductive lines are connectedto the controller 200 via a lead interface (e.g., one or more leads maybe connected to the controller 200 using an 18-pin connector).

In some embodiments, the controller 200 is operatively connected to atleast one TED in the earpieces 100A, 100B via an electrical stimulationconductive line. In some embodiments, the controller 200 is operativelyconnected to a plurality of TEDs, and the controller may be operativelyconnected to each TED via a separate electrical stimulation conductiveline. In some such embodiments, each of the plurality of separateelectrical stimulation conductive lines is bundled together into one ormore leads (e.g., two leads, with the conductive lines connected to theTEDs in the right ear being bundled separately from the conductive linesconnected to the TEDs in the left ear). In some such embodiments, theelectrical stimulation conductive lines are connected to the controllervia a lead interface (e.g., two leads may be plugged into the controllerusing a shared 18-pin connector).

In some embodiments, the controller 200 is operatively connected to atleast one TED in the earpieces 100A, 100B via a wireless connection,such as a Bluetooth connection. In some embodiments, the controller 200is configured to activate the TED 30 to deliver one or more activelycontrolled, time-varying thermal waveforms to the vestibular systemand/or the nervous system of a patient.

In some embodiments, the impedance module 222 is configured to detectand/or monitor an impedance between the two earpieces 100A, 100B. Forexample, as illustrated in FIG. 8, an electrical connector 221 is usedto electrically connect the two earpieces 100A, 100B. the electricalconnector 221 may be any electrically conductive material, such as ametal wire that may be physically connected to the earpieces 100A, 100Band connected through, for example, the cable 16 and/or controller 200as illustrated in FIG. 1.

In some embodiments, the patient module 223 is configured to analyzepatient-specific parameters and/or data. For example, the patient module223 may combine data from the waveform module 220 and the impedancemodule 222 to determine if the patient has complied with a treatmentplan based on whether the impedance values are consistent with theearpieces 100A, 100B being correctly positioned during administration ofthe treatment. In some embodiments, the patient module 223 may be usedto enter and record patient diary information, such as pain scores,occurrences of a conditions (e.g., a headache), additional treatmentsthat are being administered, and the like.

As illustrated in FIG. 8, the impedance module 222 may deliver anelectrical current via the electrical connector 221 to one of theearpieces 100A, 100B. Again without wishing to be bound by theory, it isbelieved that if the earpieces 100A, 100B are in generally good thermalcontact with the subject's ear canal, then the earpieces 100A, 100B willalso be in substantially good electrical contact with the subject's earcanal and the subject's head will substantially complete an electricalcircuit between the earpieces 100A, 100B. However, if the earpieces100A, 100B are not in good thermal contact with the subject's ear canal,then there will also be poor electrical contact with the subject's earcanal, the subject's head will not complete the electrical circuitbetween the earpieces 100A, 100B, and an open circuit will be detectedby the impedance module 122.

In this configuration, the impedance and/or capacitance value betweenthe earpieces 100A, 100B may be used to estimate the thermal contactbetween the earpieces 100A, 100B. In some embodiments, impedance and/orcapacitance values may be detected for a range of subjects to determinea range of impedance and/or capacitance values in which it may beassumed that the earpieces 100A, 100B are in sufficient thermal contactwith the subject's ear canal. When a headset is being fitted to a newpatient, the impedance and/or capacitance between the earpieces 100A,100B may be detected, and if the impedance value is within theacceptable range, it may be assumed that there is good thermal contactbetween the earpieces 100A, 100B and the subject's ear canal.

In some embodiments, when the headset is being fitted to a new patient,the impedance and/or capacitance value between earpieces 100A, 100B maybe detected and used as a patient specific baseline to determine if thepatient is later using the headset and a proper configuration. Forexample, the patient may use a headset according to embodiments of thepresent invention in a setting that may or may not be supervised by amedical professional. In either environment, the impedance module 222may record an impedance and/or capacitance value at a time that is closein time or overlapping with the time in which the treatment waveformsare delivered to the earpieces. The medical health professional or theimpedance module 222 may analyze the impedance value to determinewhether the earpieces 100A, 100B were properly fitting during treatment.In some embodiments, the impedance module 222 may be configured toprovide feedback to the user when impedance values detected on theelectrical connector 120 that are inconsistent with properly fittingearpieces 100A, 100B in good thermal contact with the ear canal. In thisconfiguration, the impedance module 222 may provide an estimation of adegree of thermal contact between the earpieces 100A, 100B and the earcanal in real-time or in data recorded and analyzed at a later time.Accordingly, patient compliance with treatment protocols may bemonitored based on the detected impedance during or close in time totreatment.

In particular embodiments, the impedance module 222 may also providefeedback to the waveform module 220, for example, so that the waveformmodule 220 may increase or decrease in amplitude of the waveform controlsignal responsive to the degree of thermal contact determined by theimpedance module 222 based on the impedance and/or capacitance value ofthe electrical connector 221. For example, if the impedance module 222determines based on the impedance value of the electrical connector 221that there is a poor fit and poor thermal contact with the ear canal,then the waveform module 220 may increase the thermal output to theearpieces 100A, 100B to compensate for the poor thermal contact. In someembodiments, the impedance module 222 may determine patient compliance,e.g., whether the patient was actually using the device duringadministration of the waveforms.

Although embodiments of the present invention are illustrated withrespect to two earpieces 100A, 100B, it should be understood that insome embodiments, a single earpiece may be used, and an electricalcontact may be affixed to another location on the user's head instead ofthe second earpiece to thereby provide an electrical circuit fordetermining impedance values and estimating thermal contact as describedherein.

As illustrated in FIG. 8, the waveform module 220 may be configured tocommunicate first and second waveforms to the TEDs 30 of the earpieces100A, 100B. It should be understood that the first and second waveformsmay be the same, or in some embodiments, the first and second waveformsmay be different such that the thermal output delivered from the TEDs 30to the earpieces 100A, 100B are independently controlled and may bedifferent from one another.

The safety monitoring module 227 my receive sensor data from theearpieces 100A, 100B, the heat sinks 50 (FIGS. 1-2), or from variouselectrical components of the system, including a power output from thewaveform module 220. The safety monitoring module 227 is configured toanalyze the sensor data or other data such as power output data todetermine if elements of the system may be operating outside of apredefined safety range and to disable or cease operation of thewaveform module 220 in the event that unsafe parameters are detected.For example, the sensor data may include temperature data from theearpieces 100A, 100B and/or the heat sinks 50 such that if the earpieces100A, 100B and/or the heat sinks 50 are operating above or below a giventemperature (for example, greater than about 50-55° C.), then the safetymonitoring module 227 ceases operation of the device, for example, byhalting the delivery of different waveforms and/or by driving theearpieces 100A, 100B to a safer temperature. The safety monitoringmodule 227 may implement safety procedures, such as halting the deliveryof different waveforms and/or driving the earpieces 100A, 100B to asafer temperature, if a voltage to drive the TED 30 is above a thresholdvalue, if the safety monitoring module 227 detects that the fans 60, 62are not properly operating, and/or if other conditions are detected thatindicate patient safety issues may occur.

In some embodiments, the power from the waveform module 220 may bedelivered to the TED 30 of the earpieces 100A, 100B via a power cable,and sensor data, for example, from the temperature sensor 40 and/ortemperature sensors positioned in other suitable locations of thedevice, such as to measure a temperature of the heat sink 50, may becommunicated to the controller 200 via a wireless connection. Such awireless sensor connection may reduce or eliminate signal interferencesbetween a power cable and the sensor signal over configurations in whichthe sensor signal would be supplied via the same cable as the power tothe TED 30. A wireless sensor signal connection to the control 200 mayalso reduce a weight of the cable and thus increase patient comfort.

Waveforms

Without wishing to be bound by theory, functional imaging studies mayindicate that there is a generally dominant laterality to caloricstimulation. See Marcelli et al., Spatio-Temporal Pattern of VestibularInformation Processing after Brief Caloric Stimulation, European Journalof Radiology, vol. 70, 312-316 (2009). Stated otherwise, cold caloricstend to activate contralateral brain regions, and warm calorics tend toactivate ipsilateral brain regions. For example, it has been found thatshort, left ear stimulation lead to right brain activation. See id.Accordingly, it is currently believed that independent dual earstimulation may allow combinations to target specific regions and/orhemispheres of the brain. For example, and again without wishing to bebound by theory, warm stimulation may increase the phasic firing rate ofthe afferents of the vestibular system, and cold stimulation maydecrease phasic firing rates. Thus, it is currently believed that thelaterality of activation for a given temperature above or below bodytemperature and a sawtooth waveform may cover a spectrum of phasicfrequencies for vestibular stimulation, and a square wave may favorlarger magnitude frequencies. Moreover, it is currently believed thatcold stimulation leads to reduced phasic firing rates and warmstimulation leads to increased phasic firing rates. In some embodiments,time-varying thermal waveforms may be selected for administration basedon a region of the brain in which stimulation is desired. In someembodiments, different thermal waveforms may be used in respective ears.For example, a warm treatment waveform that oscillates between warmtemperatures in one ear and a cold treatment waveform that oscillatesbetween cold temperatures in the other ear may increase a stimulationinto a particular region of the brain. However, it should be understoodthat any suitable combination of waveforms may be used. In someembodiments, waveforms are varied over the same or different treatmentperiods. For example, various thermal waveforms, including, but notlimited to, those described in U.S. Provisional Patent Application No.61/424,132 (attorney docket number 9767-38PR), 61/498,096 (attorneydocket number 9797-38PR2), 61/424,326 (attorney docket number9767-39PR), 61/498,080 (attorney docket number 9767-39PR2), 61/498,911(attorney docket number 9767-44PR) and 61/498,943 (attorney docketnumber 9767-45PR) may be used

In some embodiments, two eigen functions or general shapes fortime-varying thermal waveforms may be used: the square wave and thesawtooth (or triangular) wave. Both of these waveforms vary in time,which may be useful to maintain robust vestibular stimulation for timeperiods that may be therapeutically useful. In addition, these waveformsmay employ periods of stasis or continuous variability. For example, inthe case of the square wave, a specific temperature is applied to theear canal and that stimulation may set up a heat flow pattern that maybe eventually propagated over to the proximal wall of the ear canal.However, the period of statis should not be so long that the cupulaadapts to a new position, which may result in a return to the tonicfiring rate, which typically occurs in about 2-3 minutes during constanttemperature applications such as that delivered by traditionaldiagnostic caloric irrigators or other caloric devices that typically donot apply time-varying waveforms. In contrast, a sawtooth waveformconstantly varies, and thus the cupula may be always out of equilibriumand the phasic firing rate may be continuously varying. However, if thechange in temperature of the sawtooth waveform is too small or the rateof change is too fast for the bony structure of the ear to keep up, thevariations in temperature will tend to be homogenized, and aninsufficient thermal gradient may be established, for example, acrossthe horizontal semicircular canal and other vestibular structures suchas the utricle and saccule.

In some embodiments, the frequency or period of the waveform may not beconstant and/or may be irregular, e.g., so as to introduce “noise” intothe caloric stimulation. The variations in frequency/period of thewaveform can be stochastic variations (i.e., a random variation infrequency), structured variations (such as based on a function, e.g.,“1/f noise”), or monotonic variations. Although in conventionalelectrical neurostimulation, the frequency of the stimulation may berapidly varied, for calorics, the thermal conduction time may limit thespeed with which one can vary the frequency. Without wishing to be boundby theory, injecting low frequency noise (e.g., 2 Hz or less) mayimprove a therapeutic benefit. In some embodiments, the frequency/periodmay be changed from one session to the next. Moreover, the variations infrequency/period may be independently controlled such that differentperiods/frequencies may be used or varied differently in each of thepatient's ears.

In some embodiments, the time-varying thermal waveforms are sufficientto induce nystagmus over periods longer than about four or five minutesor for longer than ten to fifteen minutes or more. Nystagmus may be asmeasured by videonystagmography and/or by electronystagmography, and mayincrease or decrease or even cease for brief periods over the treatmentperiod, but may be substantially present over four or five minutes orfor longer than ten to fifteen minutes or more.

Nystagmus generally refers to involuntary eye movements enabled by thevestibulo-ocular reflex (VOR) or loop. The starting point of the loop isafferents leaving the vestibular bodies, going to the vestibular nucleiin the brainstem. From the brainstem the loop continues through thecerebellum and to the motor cortex controlling eye movements as would beunderstood by one of skill in the art. The VOR makes possible thetracking of an object with one's eyes while the head is moving, forinstance. In this case, input from the horizontal semicircular canal maybe primarily responsible for such tracking to be possible. Rotating thehead about the vertical axis deforms the cupula in the horizontal SCCand alters the tonic firing rate of the afferent nerves and innervatingthe hair cells associated with the horizontal SCC. Head rotation in onedirection increases the (phasic) firing rate above the tonic rate andhead rotation in the opposite direction decreases the firing rate.

Without wishing to be bound by theory, caloric vestibular stimulationmay provide an artificial mechanism to activate the VOR. By tilting thehead (˜20 degrees above the horizontal), the horizontal SCC is placed ina vertical orientation. Creating a differential temperature across thiscanal may result in convection currents that act to displace the cupula.Warm caloric vestibular stimulation may lead to cupular displacementsuch that the phasic firing rate increases, whereas cold caloricvestibular stimulation may lead to a decrease in the firing rate.Further, warm caloric vestibular stimulation may lead to nystagmus thatis manifested by a rapid movement of the eyes towards the simulated ear.Cold caloric vestibular stimulation may result in the rapid phase ofnystamus away from the stimulated ear. Therefore, by noting theexistence and the direction of nystagmus, it may be determined that theVOR is being activated and whether the phasic firing rate is greaterthan or less than the tonic firing rate. In some embodiments, theresults of nystagmus may be used to select a therapeutically effectivetreatment waveform, including the introduction of variations, such asnoise, as described herein.

The use of continuous caloric vestibular stimulation irrigation orstimulation at a constant temperature may induce nystagmus. However,after a time on the order of 2-3 minutes (e.g, Bock et al., “Vestibularadaptation to long-term stimuli,” Biol. Cybernetics, vol. 33, pgs.77-79, 1979), the cupula may adapt to its new, displaced position andthe phasic firing rate typically returns to the tonic rate. Thus,nystagmus will effectively cease and the vestibular nerve afferents willno longer be stimulated.

In some embodiments of the current invention, the use of time-varyingthermal waveforms enables the persistent stimulation of the vestibularnerve afferents, beyond the time period at which adaptation to aconstant thermal stimulus occurs. In contrast to continuous caloricvestibular stimulation, time-varying thermal waveforms may allow forstimulation for a longer or even an indefinite period of time. However,treatments of about 10-20 minutes may be therapeutically effective.

In one example, a sawtooth waveform going between temperatures of 34 to20° C. was applied to the right ear of a subject who was reclined suchthat his head was ˜20 degrees above the horizontal.Electronystagmography was used to measure the movement of his eyes.Segments of the time series of the nystagmus are shown in FIG. 21,demonstrating the existence of nystagmus both early in a 12 minuteperiod and near the end of the 12 minute period. Accordingly, nystagmusmay be used to confirm vestibular stimulation during a treatment period.

Although nystagmus may be used to confirm vestibular stimulation duringa treatment period, it should be understood that other techniques may beused, such as medical imaging techniques. Moreover, in some embodiments,nystagmus from the stimulation of one ear canal may be nulled bystimulation using an appropriate waveform in the other ear canal;therefore, vestibular stimulation may still occur even in the absence ofobserved nystagmus.

Example Waveforms

Exemplary waveforms that may be delivered by the TEDs 30 of theearpieces 100A, 100B by the waveform module 220 are illustrated in FIGS.9-15. The waveforms on the left side of FIGS. 9-15 are generallyadministered into the left ear, and the waveforms on the right side ofFIGS. 9-15 are generally delivered into the right ear. However, itshould be understood that the treatment waveforms may be delivered intoeither ear, e.g., so that the waveforms on the right side of FIGS. 9-15may be administered into the right ear, and the waveforms on the leftside may be administered into the left ear.

FIG. 9 illustrates in-phase square waves, with warm left ear and coldright ear stimulation, which may provide enhanced left hemisphericactivation with predominantly higher and predominantly lower phasicfrequencies. FIG. 10 illustrates in-phase square waves with warm leftand right ear stimulation, which may lead to bi-lateral hemisphericactivation with predominantly higher phasic frequencies. FIG. 11illustrates out-of-phase square waves with warm left and right earstimulation, which may lead to bi-lateral hemispheric activation withpredominantly higher phasic frequencies, but with the maximum phasicfrequency being reached at different times in the two hemispheres duringa treatment session. FIG. 12 illustrates in-phase square waves in whichwarm and cold are administered to the left ear, and warm stimulation isprovided to the right ear, which may lead to predominantly higher phasicfrequencies being achieved in both hemispheres, but also with apredominantly lower phasic frequency component in the right hemisphere.FIG. 13 illustrates out-of-phase square waves with warm and coldstimulation in the left ear and warm stimulation in the right ear, whichmay lead to bi-lateral hemispheric activation with predominantly higherphasic frequencies being achieved in both hemispheres at different timesin the treatment cycle, but also with a predominantly lower phasicfrequency component in the right hemisphere that is roughly in phasewith the predominantly higher phasic frequencies in the righthemisphere. FIG. 14 illustrates an in-phase sawtooth wave with warmstimulation in the left ear and cold stimulation in the right ear, whichmay lead to enhanced left hemispheric activation with a range of phasicfrequencies being achieved both above and below and equilibrium orunstimulated rate. FIG. 15 illustrates an in-phase sawtooth wave withwarm stimulation in both the left and right ear, which may lead tobilateral hemispheric activation with a range of phasic frequenciesabove the tonic or unstimulated rate. FIG. 16 illustrates sawtooth waveshaving an equal period with warm and cold stimulation in the left earand warm stimulation in the right ear, which may lead to bilateralhemispheric activation with a range of phasic frequencies beingachieved.

In some embodiments, different waveform shapes and/or periods may bedelivered to respective ears of the patient. For example, FIG. 17illustrates an in-phase sawtooth left ear waveform and a square waveright ear waveform that are both warm stimulations and may lead tobilateral hemispheric activation with a range of phasic frequenciesbeing achieved above the tonic rate in the left ear and predominantlyhigher phasic frequencies being achieved in the right ear. Additionalconfigurations of other “unmatched” waveform shapes and/or periods maybe used.

FIG. 18 illustrates square wave right and left ear warm square waveswith a higher frequency square wave being administered to the right ear.This may lead to bilateral hemispheric activation with predominantlyhigher phasic frequencies and with the lower frequency left ear waveformresulting in a higher phasic frequency firing of the vestibular nervethan the higher frequency right ear waveform. FIG. 19 illustrates a warmleft ear and warm right ear square wave with a time-varying period inthe left ear. The waveforms in FIG. 19 may lead to bilateral hemisphericactivation with predominantly higher phasic frequencies, but with thechanging frequency of the left ear waveform leading to a variation inhow long the higher phasic rate is maintained in the left earstimulation. FIG. 20 illustrates a square waveform of both warm and coldstimulation in the left ear with a time-varying waveform period and aregular period, warm, square wave form in the right ear. The waveformsin FIG. 20 may lead to bilateral hemispheric activation withpredominantly higher phasic frequencies in both hemispheres but withgenerally lower phasic frequencies in the right hemisphere. Thetemperature change in the left ear may lead to different phasicfrequencies being achieved (above and below the tonic rate). Thefrequency variation may affect the time over which a given phasicfrequency is achieved. The waveforms in FIG. 21 may lead to bilateralhemispheric activation with predominantly higher phasic frequencies inboth hemispheres but with generally lower phasic frequencies in theright hemisphere. The frequency variation in the left ear may berandomly changed over time or the frequency variation may be structured,for example, increasing or decreasing over time be a given rate.

It should be understood that the treatment waveforms that may beprovided are not limited to those in FIGS. 9-21. For example, the rightear stimulation and the left ear stimulation may be reversed, the shapeand/or period of the waveform may be changed, and/or the warm/coldcharacteristics may be reversed. Without wishing to be bound by anyparticular theory, functional imaging studies have shown that there maybe a dominant, but not complete, laterality to caloric stimulation. Forexample, cold caloric stimulation may have a tendency to activatecontralateral brain regions and warm caloric stimulation may have atendency to activate ipsilateral brain regions (above the vestibularnuclei in the brainstem). Marcelli et al. (“Spatio-temporal pattern ofvestibular information processing after brief caloric stimulation,” EurJ Radiol, vol 70, pg. 312-316, 2009) discusses that left ear, shortstimulation leads to right brain activation. Accordingly, independentdual ear stimulation may allow for interesting combinations to targetspecific regions and hemispheres of the brain. Moreover, warmstimulation may increase the phasic firing rate of the afferents of thevestibular system and cold stimulation may decrease phasic firing.

For example, FIGS. 9-21 generally illustrate sawtooth (or triangular)wave forms and square waveforms. It should be understood that these waveforms are illustrative, and any suitable shape of waveform may be used.Both of these waveforms vary in time, which may assist in maintainingrobust vestibular stimulation for times of therapeutic utility. Squareand sawtooth wave forms may also embody the two primary types ofvariation: periods of constancy or continuous variability. In the caseof the square wave, a specific temperature may be applied to the earcanal, which provides a heat flow pattern that is eventually propagatedover to the proximal wall of the inner ear and thus the first of thevestibular structures of interest (the horizontal semicircular canal or“SCC”). The horizontal SCC may develop a temperature gradient across itsdiameter, which may drive the convective endolymph motion and distortionof the cupula. The square wave may “switch” temperatures before thecupula accommodates a terminal position and thus ceases to alter thetonic firing rate of its associated hair cells. In the interim, apseudo-equilibrium condition may be established with heat flow. Bycontrast, the sawtooth waveform is generally constantly varying and thusthe cupula may be in a state of being always out of equilibrium, andconsequently, the phasic firing rate may be continuously varying. Apotential limitation of a sawtooth waveform is that if the amplitude (ortemperature delta) is too small or the rate of change is too fast forthe specific heat of the bony structure of the ear, the variations intemperature may be homogenized and an insufficient thermal gradient maybe established across the horizontal SCC.

Therefore, in general, the activation for a given temperature above orbelow body temperature is generally a lateral relationship, and asawtooth may be useful for covering the spectrum of phasic frequencies;and the square wave may be useful for providing the larger magnitude(farther away from the tonic firing rate) frequencies. Cold temperatures(i.e., lower than body temperatures) may lead to phasic firing below thetonic rate and warm temperatures (i.e., above body temperatures) maylead to phasic firing above the tonic rate (in the horizontal SCC).Various examples are provided in FIGS. 9-21.

It may also be noted that a variety of stimulation combinations, whichmay be provided according to embodiments of the present invention, mayaddress challenges that may be presented by electrical neurostimulators(including implanted electrode devices and transcranial magneticstimulation devices). Adaptation to neurostimulation is discussed, e.g.,by Krack et al., “Postoperative management of subthalamic nucleusstimulation for Parkinson's disease,” Movement Disorders, vol. 17, pg.5188, 2002. For instance, for an implanted neurostimulator that isgenerating a specific pulse train for many hours during the day overmany days, the tendency is for synaptic plasticity to accommodate thisnew stimulus and potentially decrease the efficacy of the therapy. Somemodern neurostimulators attempt to include adaptive changes to thestimulation to account for changes in efficacy, but such systems workunder a narrow range of parametric settings and the risk of side effectsdeveloping from changes in the stimulation pattern is significant. Sideeffects resulting from caloric stimulation according to some embodimentsof the present invention may be transient and easily observed, and thus.the prescribing medical health professional can try a range of treatmentparadigms to balance continued efficacy and low side effects.

In some embodiments, waveforms may be altered over time so as to reduceadaptation by the nervous system and provide continued efficacy overtime.

Although various examples of waveforms are provided in FIGS. 9-21,additional waveforms may be provided by varying one or more of thefollowing parameters:

Parameter Control Δ temperature Control of the TED's upper and lowtemperature ranges Δ frequency Software programming that allows time-varying waveforms to be created Vary freq. during treatment Softwareprogramming that allows time- varying waveforms to be created Vary rangeof Δ temp. Software programming that allows time- during treatmentvarying waveforms to be created Time-varying waveform Softwareprogramming that allows time- type varying waveforms to be created Phaserelationship between Timing relationship between the independent leftand right applied waveform controllers for the left and right waveformsearpieces Stochastic or structured The ability to import a designedwaveform noise modulation of into the waveform controllers waveformtemperature, frequency, or phase

Again, without wishing to be bound by any particular theory, the humanbody is currently believed to have naturally developed systems that arenot strictly periodic in terms of activation or neuronal spiking. Forexample, the power spectrum of EEG measurements has a slope that isclose to 1/f (the inverse of the frequency). This may imply that thedynamical system underlying the EEG spectrum (the summation of allcortical neural activity) has properties like scale similarity (one partof the EEG power spectrum, when expanded, looks like the whole spectrum)and self-organized criticality, which may imply that the state of thesystem is in a sense poised between predictable periodic behavior andunpredictable chaos (see, e.g., Buzsaki, “Rhythms of the Brain,” OxfordPress, 2006). There are also well-studied pathological conditionsreflecting abnormal synchronous behavior, such as cardiac fibrillationand epileptic seizures. Neurostimultors have made use of random(stochastic) or aperiodic (structured noise, like 1/f noise) pulsesequences to evaluate enhanced efficacy. For example, instead ofmaintaining a 100 Hz electrical firing rate the frequency might bevaried with structured or unstructured noise. Caloric vestibularstimulation may act to modify the phasic firing rate of the hair cellsindirectly by, primarily, modulating the position of the cupula. Thus,to introduce noise into the phasic firing rate, a time-varying thermalwaveform may be provided to move the cupula in a way such that thetransduced effect is to produce the desired phasic firing frequencyspectrum. As a specific example, the summation of five sine waves isconsidered. A sine wave may be used as a basis function from whichtime-varying thermal waveforms may be created. In fact, the sawtoothwave considered herein may be provided by a series of sine waves (e.g.,a Fourier series). The amplitude as a function of time is:

${A(t)} = {\frac{2}{\pi}{\sum\limits_{k = 1}^{\infty}\; \frac{\sin \left( {2\pi \; {kft}} \right)}{k}}}$

Now, for the example of the summation of five sine waves, 1/f weightingis included as follows:

A(t)=(1/f ₁)*sin(2p f ₁ t)+(1/f ₂)*sin(2p f ₂ t)+(1/f ₃)*sin(2p f ₃t)+(1/f ₄)*sin(2p f ₄ t)+(1/f ₅)*sin(2p f ₅ t)

wherein values of f₁₋₅ are chosen as follows: f₁=0.003 Hz, f₂=0.004 Hz,f₃=0.005 Hz, f₄=0.006 Hz and f₅=0.008 Hz, and the sign and offset of thefunction is adjusted. This results in the temperature profileillustrated in FIG. 22.

As discussed herein, the change in phasic firing rate is currentlybelieved to be approximately linear with the change in caloricstimulation temperature, and therefore, the phasic rate may be changedaccording to the spectral character of the caloric waveform. Thus, the1/f-weighted waveform above may induce 1/f-weighting into the phasicfrequency spectrum. It should be understood that additional oralternative weighting coefficients may be used to provide time-varyingwaveforms according to embodiments of the present invention.

It should be understood that the treatment waveforms may be used as anadjuvant treatment, alone (e.g., monotherapy) or as neoadjuvant therapy(e.g., the delivery of a treatment waveform before or after anothertherapy).

Example Impedance Measurements

An Agilent® LCR meter was connected to metallic parts that roughlymatched the diameter and contour of the earpieces described herein.Resistance values were taken at 1 KHz, within 10 seconds of insertion,and with either firm pressure on the ear or light pressure on the ear asfollows:

Firm Pressure (kilo-ohms) Light Pressure (kilo-ohms) 50 Typical: 150-20040 46 Typical 40-50

Capacitance values were taken at 1 KHz, within 10 seconds of insertionfor firm pressure on the ear or light pressure on the ear for threesubjects as follows:

Firm Pressure (pF) Light Pressure (pF) 3500 1700 3500 1700 3500

Comparative capacitance values were measured on the pinna at ˜600 pF andon the outer ear canal at ˜500 pF. Therefore significantly higher valuesfor both capacitance and resistance were measured when firm pressure wasapplied to the device to improve contact with the ear canal.

In addition, three different subjects were tested for both capacitanceand resistance with firm pressure, which yielded values within aconsistent range. The test values were C=3.5-3.9 nF and R=30-32 k-ohmfor the first subject, C=3.7-4.0 nF and R=20-24 k-ohm for the secondsubject, and C=3.5-4.0 nF and R=35 k-ohm for the third subject.

Thus, the capacitance values seemed generally consistent when hardpressure was used. The resistance values seemed more variable, but stillprovided a consistent range of values with firm pressure. The valuesrecorded when one of the ear probes was placed on the pinna or outer earcanal were significantly different from both firm pressure and lightpressure reading well into the canal. Such measurements may be used,e.g., by the impedance module 222 in FIG. 8 to verify earpiece placementand thermal contact and/or to verify patient compliance with applyingthe treatment waveforms during operation of the earpiece in the earcanal.

Example Treatment Protocols

Embodiments according to the present invention will now be describedwith respect to the following non-limiting examples

Example 1 Long Duration Square Wave Administration

A male subject in his forties and good health, naïve to CVS treatment,was administered cold caloric vestibular stimulation to his right ear ina square waveform pattern. The pattern was of cooling to 10 degreesCentigrade (as compared to normal body temperature of about 37 degreesCentigrade) as a “step” function or “square wave” with one symmetricsquare wave being delivered for a time period of 20 minutes. The subjectwas observed by others to be slurring his words, and was asked to remainseated for a time of two hours following the treatment session as aprecaution. Otherwise, no long-term deleterious effects were observed.

Example 2 Sawtooth Wave Administration

The same subject described in EXAMPLE 1 was subsequently treated byadministering cold caloric vestibular stimulation to the right ear in asawtooth waveform pattern of cooling to 20 degrees Centigrade (ascompared to normal body temperature of about 37 degrees Centigrade) in asymmetric sawtooth waveform pattern, without gaps, at a frequency of onecycle or waveform every five minutes, for a total duration ofapproximately 10 minutes and a delivery of a first and second waveform.Unlike the situation with the square wave pattern described in Example1, the subject continued to perceive the temperature cycling up anddown.

Example 3 Maximum Waveform Amplitude

The same subject described in Examples 1-2 was administered cold caloricvestibular stimulation to the right ear as a sawtooth cooling waveformat different amplitudes in a titration study. A maximum perceivedsensation of cyclic cooling was perceived at a peak amplitude of about17 degrees Centigrade (or cooling from normal body temperature to atemperature of about 20 degrees Centigrade). Cooling beyond this did notlead to additional gains in the sensation of cyclic cooling perceived bythe subject.

Example 4 Minimum Waveform Amplitude

Modeling of the human vestibular system indicates that the cupula (thestructure within the semicircular canals pushed by the movement of fluidtherein and which contain hair cells that convert the mechanicaldistortion to electrical signals in the vestibular nerve), is stimulatedby caloric vestibular stimulation at chilling temperatures of 5 or 7degrees Centigrade below body temperature.

Example 5 Maximum Waveform Frequency

Modeling of the human vestibular system indicates that a slew ratefaster than 20 degrees Centigrade per minute (which would enable one 20degree Centigrade waveform every two minutes) is not useful because thehuman body cannot adapt to temperature changes at a more rapid rate.While maximum frequency is dependent in part on other factors such aswaveform amplitude, a maximum frequency of about one cycle every one totwo minutes is indicated.

Example 6 Minimum Waveform Frequency

Modeling of the human vestibular system indicates that a continuous,time-varying waveform is most effective in stimulating the vestibularsystem, as stagnation and adaptation of the cupula is thereby minimized.While minimum frequency is dependent in part on other factors such asthe waveform amplitude, a minimum frequency of about one cycle every tento twenty minutes is indicated.

Example 7 Treatment Session Duration

To permit delivery of at least a first and second waveform, a durationof at least one or two minutes is preferred. As noted above and below,results have been reported by patients with treatment durations of tenand twenty minutes. Hence, as a matter of convenience, a treatmentsession duration of not more than 30 or 40 minutes is preferred (thoughlonger sessions may be desired for some conditions, such as acute caresituations).

Example 8 Treatment of Migraine Headache with Sawtooth Waveforms

A female patient in her early fifties with a long standing history ofmigraine suffered an acute migraine episode with symptoms that consistedof a pounding headache, nausea, phonophobia, and photophobia. Right earcold caloric vestibular stimulation was performed using the sawtoothwaveform, essentially as described in Example 2 above, with atemperature maximum of 17 degrees (chilling from body temperature) for10 minutes (for a total delivery of two cycles). At the conclusion ofthe treatment the patient reported that her headache and associatedsymptoms were no longer present. At a reassessment one day later, thepatient reported that the headache had not returned.

Example 9 Treatment of Diabetes with Sawtooth Waveforms

The same subject described in examples 1-3 suddenly developed an episodeof extreme urination (10 liters per day), thirst for ice water, andassociated fatigue. Urinary testing suggested the onset of diabetesmellitus, for which there was strong family history.

The patient's initial weight as taken at his primary care physicianindicated a recent 20 pound weight loss. The first attempt to obtain aglucose reading from the patient resulted in an out of range result(this result typically occurs with glucose levels in excess of 600mg/dl). The patient was hospitalized and received hydration and IVinsulin therapy. The patient's first glucose level after this treatmentwas 700 mg/dl. The glucose level were brought down to approximately 350and treatment with an oral antihyperglycemic agent was initiated.

Follow-up care after hospital discharge with the subject's primary carephysician. expanded the oral antihyperglycemic agent therapy to includeboth metformin and JANUVIA™ sitagliptin. In addition, a strict exerciseprogram of 30-45 minutes 5 to 6 days per week and diet control wereinstituted. Daily glucose levels via finger stick were taken 2 to 3times per day.

At this point the patient's baseline hemoglobin A1c (Hb A1c) level was9.8%, as compared to normal levels of 5 to 6%.

The patient then began daily treatment with caloric vestibularstimulation. The treatment was carried out for a time of ten minutes,once a day for about a month, after which the treatment was continuedtwo to three times a week for three additional months (with eachtreatment session being about 10 minutes in duration). The caloricvestibular stimulation was delivered to the patient's right ear, as asawtooth cooling waveform as described in Example 2. At the conclusionof these treatments, the patient's HB A1c level was 5.3%. As a result,the patient was removed from all hypoglemic agents.

Most oral antihyperglycemic agents lower a patient's Hb A1c level byapproximately 1 to 2% (see generally S. Inzucchi, Oral AntihyperglycemicTherapy for Type 2 Diabetes, JAMA 287, 360-372 (Jan. 16, 2002)). Incontrast, this patient's initial value was 9.5, and dropped to 5.3.

Example 10 Alternate Waveform Shapes

The sawtooth waveform described in the examples above was symmetric andlinear, as illustrated in FIG. 23A, where line dashed line “n”represents the subject's normal body temperature (typically about 37degrees Centigrade). Modeling of the vestibular system indicates thatwaveforms of similar amplitude and frequency, but with a variation inshape, are also effective, such as the “logarithmic” or “convex”waveform of FIG. 23B, and the “exponential” or “concave” waveform ofFIG. 23C. All waveforms generally include a leading edge (“le”), atrailing edge (“te”), a peak (“p”) and a trough (“t”).

While FIGS. 23A through 23C all show three consecutive waveforms of thesame shape, amplitude, and frequency, the consecutive waveforms can bevaried in shape as shown in FIG. 23D, and can be varied in amplitude orduration as well (preferably each consecutive waveform within theparameters noted above), to produce still additional waveforms andsequences of waveforms which are useful in carrying out the presentinvention.

In addition, while the waveforms of FIGS. 23A through 23D are shown ascontinuous, minor disruptions can be included therein, such astruncations (“trn”; for example, as shown in FIG. 23E) or vertical cuts(“ct”; for example, as shown in FIG. 23F) to produce still additionalwaveforms and sequences of waveforms which are useful in carrying outthe present invention.

The peak for all waveforms of FIGS. 23A-23F is cooling by 17 degreesCentigrade from normal body temperature to a temperature of 20 degreesCentigrade, and the trough for all waveforms is a return to normal bodytemperature, giving an amplitude of 17 degrees Centigrade. The frequencyfor all illustrated waveforms is 1 cycle (or one complete waveform)every five minutes. While 3 cycles of the same waveform are illustratedfor clarity, note that in some of the examples above only two cycles aredelivered over a total treatment or session duration of ten minutes.

Example 11 Patient Orientation

It was noted that a patient who was sitting up (watching television) andreceiving a cold caloric vestibular stimulation (CVS) treatment reportedperceiving a different effect than perceived in prior sessions. Uponreclining to about 45 degrees, she did receive the earlier effect.

The “standard” angle of recline for diagnostic CVS is about 60 degrees(or equivalently 30 degrees above horizontal). The reason for thispositioning is that the “horizontal” SCC is tilted up by about 30degrees (higher on rostal side) (More recent x-ray measurements put theangle at closer to 20+/−7 degrees.) The intent with diagnostic CVS is toreorient the horizontal SCC so that it is substantially vertical, thusmaximizing the effect of the convective flow set up by calories.

Hence, if the subject is reclined to about 20 degrees above horizontal(and supine), then a cold stimulus leads to inhibition or a phasic rateless than the tonic rate. For a warm stimulus, this situation isreversed (phasic rate increases above tonic).

Further, cold simulation tends to activate principally the contralateralbrain structures whereas hot leads to principally ipsilateralactivation. For example, in V. Marcelli et al. (Eur. J. Radiol. 70(2):312-6 (2009)), the authors did a left ear, cold stimulation by waterirrigation and saw right-side activation in the brainstem, cerebellum,etc. The patient was presumably nearly reclined in the MRI magnet.

Empirical tests and modeling indicate that approximately 20 degreesCentigrade absolute cooling (17 degrees Centigrade below bodytemperature) is the lower limit beyond which the cupula is maximallydeformed and therefore the phasic rate change is maximal. On the warmingside, more than about 7 degrees or so above body temperature becomesuncomfortable. This level of temperature heating within the ear canalwill not lead to maximal deformation of the cupula. Therefore, there isan asymmetry in terms of ability to span the full frequency spectrum ofphasic firing rates. However, the increase in the phasic firing rate isnot constrained in the manner of a decrease—that is, the phasic firingrate can only approach zero, relative to the tonic rate of roughly 100Hz, whereas the phasic rate can exceed 200 Hz.

Since inverting the patient changes the sign of theinhibitory/excitatory motion of the cupula, the following can be seen:Using a cold stimulus, of 20 degrees absolute, but now orient thepatient so that his head is tilted forward by from 75 to 20 degrees fromthe vertical position. This will invert the horizontal SCC relative tothe image above and now the cold stimulus will result in an excitatoryincrease in the phasic firing rate. For clarity, tilting the headforward by 20 degrees makes the horizontal SCC substantially horizontal.Tilting beyond that now starts to invert it so that at 110 degrees(tilted forward), the horizontal SCC will be in a vertical orientation,but now 180 degrees flipped from what is used in conventional diagnosticcaloric vestibular stimulation. So, the “general rule” for treatment ofhaving the patient reclined by 45-90 degrees can be expanded to include“tilted forward” by 75-120 degrees.

Thus a protocol is seen where, using only cold stimulus, one can coverthe entire range of phasic firing rates simply by reorienting thepatient at the appropriate points during the time course of treatment.

Note that this type of inversion should also lead to an inversion in theside of the brain that is primarily activated. Specifically, if coldstimulation leads to principally contralateral activation in the“rightside up” orientation, then it should lead to principallyipsilateral activation in the “upside down” orientation.

Example 12 Thermal Modeling of Caloric Vestibular Stimulation

Equation (4) of Proctor et al. (Acta Otolaryngol 79, 425-435, 1975) canbe extended for an arbitrary sequence of heating and/or cooling steps.Equation (4) is a fairly simple usage of the 1-dimensional diffusionequation. Therefore, the model is not exact. The temperature differenceacross the horizontal canal (i.e., the thermal driving gradient) isapproximated:

$\begin{matrix}{{{\Delta \; T} = {{\frac{A_{1}}{\sqrt{t}}^{{- B}/t}} + {\frac{A_{2}}{\sqrt{t - t_{1}}}^{{- B}/{({t - t_{1}})}}} + \ldots \mspace{11mu} + {\frac{A_{n}}{\sqrt{t - t_{n}}}^{{- B}/{({t - t_{n}})}}}}}{\text{where:}\mspace{14mu} \begin{matrix}{A_{n} = \frac{- {LT}_{n}}{\sqrt{\pi \; a}}} \\{and} \\{B = \frac{x^{2}}{4a}}\end{matrix}}} & (1)\end{matrix}$

L=distance across horizontal canal (mm); default=6

T_(n)=difference between applied temperature and previous temperature (°C.)

a=“thermal diffusivity” of temporal bone (mm2/sec); this may vary inpatients, but compact bone paths will dominate the thermal. Theliterature lists values from 0.14-0.25, but this is based on the onsetof nystagmus as the “stimulation time.” Marcelli et al. showed a muchfaster, actual brainstem activation time after CVS, which did not relateto the onset of nystagmus. Literature estimates for the thermaldiffusivity of hard bone range from 0.45-0.55 to 1.6. A value of 0.5 isassumed here, based on x-rays of the compact, wet bone in the region ofinterest.

x=the effective thermal distance (mm) between external ear canal and theedge of horizontal semicircular canal; default=7.5 mm

ΔT=the temperature difference across the semicircular canal (° C.);distal minus proximal temperature.

t_(n)=time at which new stimulus starts.

Default values for the constants are listed next to the definitions. CVSapplication times that are short compared to the response time of thepatient may not be very different from a longer pulse at a lowertemperature due to thermal smoothing effects. Literature reports of themaximum phasic firing rate are about 100 Hz. That is, +1-100 Hz awayfrom the tonic firing rate, which is on the order of 100 Hz. The maximumdeformation of the cupula at its center is, correspondingly, about 77microns. Thermal gradients that imply a deformation greater than thisvalue would tend to lead to saturation of the phasic firing rate. At theother end of the scale, the minimum detectable volume change in the SCCis on the order of 25 picoliters and this corresponds to a change in thephasic rate of roughly 0.5 Hz. This indicates a minimum temperaturegradient across the SCC of ˜0.02° C. The obvious requirement is that thebody's homeostatic temperature regulation must ensure a constanttemperature across the 6 mm wide canal to a value on that order.

Another simplification used in the model was to ignore the temperaturedependence of the bulk coefficient of thermal expansion of water (withthe simplifying assumption that endolymph has roughly the thermalproperties of water). This assumption will lead to an apparentsaturation of the phasic firing rate at higher temperature (roughly 27°C.) than will actually occur. Below body temperature, the phasic ratemay not saturate until the lower 20's.

The volume of the horizontal SCC is estimated to be: 3.2E-3 cc. Thechange in volume due to a temperature difference ΔT is: 3.8E-4*3.2E-3*ΔT=1.22E-6 ΔT.

The volume of the “lens” of the cupula when deformed to its maximal(saturation of the phasic firing rate) extent is roughly: 4.4E-6 ccTherefore, the change in the phasic rate: Δf=27.7*Δ T in Hz.

The relationship between the applied thermal waveform and the phasicfiring rate of the afferents of the vestibular branch of the 8th cranialnerve can thus be modeled for a square waveform stimulus (such as inExample 1 above), and for a time-varying, saw tooth, waveform stimulus(such as in Example 2 above).

It was noted that there is little distortion of the time-varyingwaveform of, as compared to the square waveform, because the body cantrack the more gradual temperature changes.

There is a tendency for the values to skew a small amount vertically(e.g., the temperature delta goes slightly above body temp at points).This effect appears to be non-physical and is simply a limit of theapproximate model employed. The same appears true of the firing rategoing positive.

The “tips” of the sawtooth waveforms appear to exceed the maximum changein phasic firing rate of 100 Hz (this is seen in the square wave aswell). This may be because the coefficient of thermal expansion of theendolymph changes with temperature and was not corrected in the modelabove. This would result in an overestimate of the firing rate for agiven temperature in the plot. Therefore, the firing rate may not, infact, saturate (i.e., will stay below a delta of 100 HZ) at 20 C. Theloss of a sense of improvement reported in Example 3 above fortemperatures below about 17 to 20 degrees Centigrade may be due to thecupula of the vestibular canal “pegging” (achieving its maximal physicaldistortion) and the firing rate saturating.

Example 13 Treatment of Chronic Migraines and Refractory Depression

A female subject was a headache sufferer with a 10-year history ofdebilitating, chronic migraines, the last five being refractory. She hadfailed all pharmaceutical interventions. The patient underwent anoccipital nerve stimulator implant for headaches, with goodsymptom-management for approximately one year, at which point the devicewas no longer effective. Co-morbid with her migraine headaches wasdepression, which was only partially responsive to pharmaceuticalmanagement. Subject was placed on disability from her employment.

The subject was treated using a five-day therapy paradigm consisting ofdaily treatments comprising a square waveform pattern of cooling to 20degrees Centigrade, at a frequency of one cycle every ten minutes, for atotal duration of ten minutes while the patient was in a reclinedposition of thirty degrees above horizontal. Video images of the subjectwere captured before, during and after each treatment session and wereused to assess the effectiveness of the treatment (e.g., by assessingthe patient's mood).

For all active, in-process migraine episodes, within 5-15 minutes aftercompletion of a treatment, subject experienced pain attenuation. Chronicheadache indication was alleviated on the 4^(th) day of treatment, withconcurrent progressive improvement in her mood over the course of thefive days. The treatment course peaked at day 5. The subject becamepain-free, with complete resolution of mood symptoms. She remainedpain-free for 63 days after the therapy was completed, at which time hermigraine headaches began to recur, but without return of clinical moodsymptoms.

The five-day therapy paradigm was repeated. The subject responded morequickly to this second longitudinal therapy, with her chronic headachesdisappearing on the 3^(rd) day of treatment. She remained pain-free forfive weeks.

Later, the patient was treated with a sawtooth waveform (lowertemperature of 20° C.) employing a daily treatment duration of 10minutes. By the end of the treatment week, the patient was pain free(using a 0-3 pain scale where 3 is severe, 2 is moderate, 1 is mild, andzero is no pain). Charted pain scores (not shown) showed improvementafter treatment. All CVS treatments were to the right ear using coldstimulation. Additionally, after each treatment week, the patient stayedpain free for times varying from 2-9 weeks. The patient additionallyreported feelings of high energy and resolution of co-morbid depression.

Example 14 Treatment-Associated Dizziness in Migraine Patient

The same subject described in example 8 had right ear CVS treatmentusing a heating, to approximately 42-43 degrees, sawtooth waveform for10 minutes, with a contiguous repeat for an additional 10 minutes. Thetreatment was effective in resolving her acute migraine pain.Additionally, the treatment had a soporific effect but also causedslight dizziness. The subject did not note the feeling of dizziness inexample 8 using cold stimulation.

Example 15 Treatment of Cluster Headache and Treatment-AssociatedDizziness

The same subject described in example 1 underwent the same CVS treatmentdescribed in example 14. He too reported a feeling of slight dizzinessthat was not apparent during cold CVS stimulation.

Example 16 Vestibular Migraine Treatment in Female Patient

A female subject in her late 30's had a history of migraine withassociated vertigo (vestibular migraine). The subject has a history ofvestibular dysfunction and slight co-morbid depression. The subject wastreated on a near daily basis, between 20-40 minutes per day, with coldstimulation (down to 20° C.) CVS before switching to warm CVS, with amaximum temperature of 48° C. All CVS treatments used a sawtooth patternwith left-ear stimulation due to more severe vestibular dysfunction inthe right ear. This subject did not note dizziness as a side effect ofthe warm CVS treatment, suggesting that her vestibular system, due todysfunction, is more immune to CVS (and thus she must treat moreaggressively to gain benefit). A parent of the subject commented on achange in the subject's speech and “spirit” during phone conversationswhile using cold CVS. The switch to warm CVS resulted in additional moodand motivational elements. Colleagues commented on enhancedinterpersonal interactions and an increased sense of confidence. Thesubject stated: “for the last couple of year I've felt as if my brainhas burnt out, it feels so much better since the warm treatments.”

Example 17 Vestibular Migraine Treatment in Male Patient

A male in his 40's developed sudden onset migraine with vestibulardysfunction that led to effective disability and inability to go towork. The subject was not helped by medications and sought the advice ofmultiple physicians at two prominent academic research hospitals. Thesubject was treated on a near daily basis for 10-20 minutes a day withcold CVS (down to 20° C.) CVS before switching to warm CVS, with amaximum temperature of 42° C. The subject, like the subject in example16, did not experience dizziness with the introduction of warm CVStreatments, possibly associated with the vestibular dysfunctionaccompanying his migraines. CVS treatments are soporific for thispatient. The subject's wife notes a pronounced change since CVStreatments were started. Whereas prior to CVS treatment the subject wasloath to get out of bed, since CVS treatment the subject has returned topart-time work with his employer.

Example 18 Treatment of Diabetic Patient with Warm Sawtooth Stimulation

The same subject described in example 9 switched from cold CVS to warmCVS for the control of his type II diabetes. He treated with a sawtoothwaveform that oscillated between 34 and 43° C. The average heating slewrate was typically above 40° C./min and the average cooling slew ratewas typically greater than 10° C./min. Since commencing CVS therapy, thesubject has stopped taking medications, which were previously necessaryto maintain serum glucose near a normal range. At the time of diagnosis,the subject's A1c value was 9.8. At the time shown at the end of thechart below, that value was reduced to 5.6 (again, with no medications).A1c is viewed as a better long-term marker of diabetes control thanserum glucose (it doesn't fluctuate). The normal range is about 4-6. Fordiabetics, the recommendation is that anything below 7 is a good target.A record of the subject's serum glucose readings (not shown) indicatedpossible additional improvement realized with the switch from cold towarm CVS in terms of reduced variability. The subject also had agingival abscess during the period shown and such infections can lead tooxidative stress and impaired glucose control (see generally J.Southerland et al., Diabetes and Periodontal Infection: Making theConnection, Clinical Diabetes 23, 171-178 (2005)). The infection did notdisrupt the subject's glucose maintenance.

Glucose readings taken at 7 AM and 10 PM; CVS treatment in evening.Treatment 1: 34 to 17 degree C. sawtooth waveform, 20 minute duration.Treatment 2: 34 to 43 degree C. sawtooth waveform, two 20 minutetreatment per day. Glucose levels are more controlled with treatment 2.No other diabetes medications were in use during the testing period.

The subject reported that the warm sawtooth CVS differed slightly fromthe cold sawtooth CVS in that it appeared to have increased potency asnoted by the feeling of increased dizziness and mild nausea, whichappear consistently with each treatment. Glucose levels tend to drop10-30 points approximately 60 minutes or more after the treatment. Thesubject reported that combining exercise in proximity to the TNM therapyappeared to cause a glucose decrease of 30 to 50 points.

Example 19 Treatment of PTSD Patient

A male in his mid 60's was wounded three times as a Medic in Vietnam andhad a history of post-traumatic stress disorder. His manner is describedas introverted and his mood depressive. After the commencement of coldCVS treatments, the subject's wife reported that he started becomingmore extroverted. She reported that “she did not know who this personwas speaking to her this morning”; that he was planning getting togetherwith friends; that usually he would only do this if forced; that heexpressed interest in going to Africa for a photo safari; that shestarted thinking “where is my husband?” After a second treatment, thesubject reported continuous sleep throughout the night (usually he wouldusually wake up 3-4 times). He commented that “insomniacs should usethis.” The subject reported feeling energized. The subject was usuallyunable to recall dreams, but awoke with visual flashback of events inVietnam, not unpleasant just old visual memories, and returned to sleep.The subject traditionally avoided driving but now is driving withsubstantially less hesitation. The subject is a serious amateur painterand both the subject and his spouse report significant positivedevelopments in his painting style and productivity since commencementof his CVS. Upon interruption of CVS therapy, PTSD symptoms graduallyreturned almost to baseline one week after CVS stopped.

Example 20 Treatment of Diabetes in a PTSD Patient

The patient of example 19 has type II diabetes. After the commencementof CVS therapy he became much more responsive to oral hypoglycemics, hashad to cut dose significantly (data not shown).

Example 21 Alternative Waveforms in Treatment of Diabetes and ClusterHeadaches

The patient described in example 18 above was administered threedifferent waveform CVS stimuli, as follows:

A: Cooling, by approximately 22-23 degrees, with a spike waveform for 10minutes with a contiguous repeat for an additional 10 minutes.

B: Heating, to approximately 42-43 degrees, with a spike waveform for 10with a contiguous repeat for an additional 10 minutes.

C: Cooling, to approximately 22-23 degrees, with a spike waveform for 10minutes as illustrated in connection with A above, followed immediatelyby heating, to approximately 42-43 degrees, with a spike waveform for 10minutes as illustrated in connection with “B” above.

The treatments seemed to have a bimodal pattern of efficacy based uponcooling or heat cycles. Both modes seem to induce a sense of motion andmild nausea associated with enhanced therapeutic efficacy for thetreatment of cluster headaches and the stabilization of type II diabetesin this subject. Pattern A appeared to be the most efficacious.Increasing cycle times to thirty minutes does not appear to confer anadditional benefit.

Example 22 Induction of Prolonged Nystagmus by Waveform CVS

Nystagmus is the name given to involuntary eye movements enabled by theso-called vestibulo-ocular reflex (VOR). CVS provides an artificialmeans to activate the VOR. By tilting the head (˜20 degrees above thehorizontal), the horizontal SCC is placed in a vertical orientation.Creating a differential temperature across this canal results inconvection currents that act to displace the cupula. Warm CVS leads tocupular displacement such that the phasic firing rate increases whereascold CVS leads to a decrease in the firing rate. Further, warm CVSresults in nystagmus that is manifested by a rapid movement of the eyestowards the simulated ear. Cold CVS results in the rapid phase ofnystamus away from the stimulated ear. Therefore, by noting theexistence and the direction of nystagmus, one may determine that the VORis being activated and whether the phasic firing rate is greater than orless than the tonic firing rate.

The use of continuous CVS irrigation or stimulation at a constanttemperature will induce nystagmus, but after a time on the order of 2-3minutes (e.g, Bock et al., Vestibular adaptation to long-term stimuli,Biol. Cybernetics 33, 77-79 (1979)), the cupula will adapt to its new,displaced position and the phasic firing rate will return to the tonicrate. Thus nystagmus will effectively cease and the vestibular nerveafferents will no longer be stimulated.

It is an aspect of the current invention that the use of time-varyingthermal waveforms enables the persistent stimulation of the vestibularnerve afferents, beyond the time period at which adaptation to aconstant thermal stimulus occurs. In this example, the present inventionhas been used to generate nystagmus over a 12 minute period as measuredby videonystagmography and by electronystagmography. A sawtooth coolingwaveform going between temperatures of 34 to 20° C. was applied to theright ear of a subject who was reclined such that his head was ˜20degrees above the horizontal. Electronystagmography was used to measurethe movement of his eyes, and demonstrated the existence of nystagmusboth early in a 12 minute period and near the end of the 12 minuteperiod (data not shown).

Example 23 Effect of CVS on Regional Cerebral Blood Flow (rCBF)

The purpose of this Example is to find a robust marker of successful CVSinduction of relevance to neurological treatments. The study is beingperformed on rats using a modified version of a dual ear CVS unit.Specifically, ear bars that are connected to TEC's are placed in the earcanals of rats that have been anesthetized. The device has dual earstimulation capability.

Methods and Results:

Single ear CVS: Rat #9 received a sawtooth waveform in the right earthat oscillated between 36 and 14° C. for 60 minutes (not shown). Therat was anesthetized with isoflurane. It should be noted that anesthesiamay lessen the effects of CVS to a degree. The rat was orientedhorizontally, which places the horizontal semicircular canal in thevestibular bodies at a roughly 30 degree tilt upwards on the anteriorside. After the end of the 60 minute right ear stimulation, the samecaloric waveform was then applied to the left ear. The response of theregional cerebral blood flow was measured on the right parietal regionof the skull via a laser Doppler probe affixed to the skull. Roughly 30minutes after the start of right ear CVS, the oscillation in blood flowbecame pronounced. The period of the sawtooth temperature waveform is1.9 minutes. As observed (using nearest neighbor averaging), the periodof the modulation in blood flow is longer, by about 30 seconds onaverage (data not shown). This suggests that the driving force (the CVS)leads to modulation of the blood flow via a mechanism that stays in anon-equilibrium state. That is, the rat's response does not simply matchthe period of the CVS waveform and is instead adapting to itdynamically. At the end of right ear CVS, the oscillations stop. Roughly35-40 minutes after the start of left ear CVS, clear oscillations onceagain appear, though diminished in amplitude relative to right earstimulation. This is presumably due to the fact that left earstimulation has a weaker effect on blood flow in the right portion ofthe brain. Serrador et al. (BMC Neuroscience 10, 119 (2009)) note that“connections have been found between the vestibular nuclei and thefastigial nucleus . . . followed by vasodilatory connections to thecerebral vessels.”

Control Run:

The CVS device was placed on the rat, but was not activated. Nooscillations in rCBF were seen (the downward drift in the flow data isdue to a slight shift in the baseline of the probe).

Dual Ear, Same Waveform:

Rat #12 had CVS delivered to both right and left ears simultaneously(not shown). The waveforms were not tied in phase and tended to becomeout of phase during the bulk of the 60 minute treatment period. Nomodulations in rCBF were manifested (data not shown).

The dual ear stimulation data suggest that the application of the samewaveform to both ears simultaneously acted to cancel out any netmodulatory effect on rCBF. However, it is still the case that the samestimulation was given to the vestibular nuclei as when only single earCVS was used. Nystagmus; would also not appear if the same CVSstimulation were applied to both ears since the phenomenon, mediated bythe vestibulo-ocular reflex (VOR), requires a differential input to thetwo horizontal SCC's. Thus the absence of rCBF modulation does not meanthat the fastigial nuclei (both nuclei for dual ear CVS) are not beingstimulated. Rather, their combined activation yields no net effect onrCBF. Since modulation of rCBF is not a necessary aspect of CVS inducedneuroprotection (it is a marker of CVS induction), CVS therapy mayactually be as or more effective with dual ear stimulation.

Dual Ear, Different Waveforms:

Run 17 simultaneously applied a 34 to 44 C sawtooth waveform to theright ear (period of ˜40 seconds) and a 34 to 13 C sawtooth (period˜1.7min) to the left ear (not shown). In this case, flow modulations wereseen and they persisted well past the end of the CVS treatment period(not shown). In this case the flow effect, with different temperaturesapplied, not only was present but continued to oscillate after the endof the active CVS treatment.

Summary:

The vestibular systems of all mammals act in the same way. Therefore,the results of the rat study discussed above has implications for humanCVS therapy as well. The conclusion from the study is that the mostlikely cause of the modulation seen in rCBF is that CVS does stimulatethe fastigial nucleus in the cerebellum.

Example 24 EEG in Rats as a Metric of CVS Efficacy

EEG is useful in identifying cortical activation associated with CVS.Therefore, EEG is useful as a non-invasive means to titrate CVS therapy.This report summarizes EEG data acquired in a rat study.

Methods and Results:

The report on regional cerebral blood flow changes in a rat duringvarious CVS treatments has been generated. In this summary, EEGelectrodes were placed in the scalp of the rat, differential pairs beingapplied on either side of the midline of the skull. (data not shown).

Discussion

The activity observed in the theta band was markedly different betweenthe 3 states. For the low flow state, activity was depressed. The highflow peaks were shifted to lower frequencies as compared to the baseline(pre-CVS). In the 0-40 Hz plot, the high and low flow peaks in thelow-30 Hz range overlap whereas the baseline peak is shifted (this islikely due to a difference in somatosensory perception during CVS versuspre-CVS). The sensitivity of EEG spectra to the details of CVS deliverysuggest that EEG is an effective tool for evaluating the differencebetween CVS waveforms and for titrating them.

Example 25 Heart Rate Variability (HRV) as a Metric of CVS Efficacy

Heart rate variability seems to be a significant marker of health andsystems for measuring it non-invasively are becoming common. This reportdescribes the use of the ithlete, a commercial HRV measurementinstrument that runs as an smartphone software program, or “app.”

Methods and Results:

The subject is a 40-45 year old male diagnosed with seasonal clusterheadaches. The device used to measure HRV is the ithlete (HRV Fit Ltd.,Hants UK)) which uses an iPhone as the recording/readout device and achest strap with sensors that monitor heart rate. The HRV parameter iscalculated via a proprietary algorithm that takes the raw heart ratedata as input. Note: of course there are many devices that will measureHRV and the ithlete was chosen only as a low cost and convenient system.Proper HRV is used as a metric of proper cardiac health (good healthimplies adequately high HRV; e.g. Malik, “Heart rate variability:standards of measurement, physiological interpretation, and clinicaluse,” Eur. Heart Journal, vol. 17, pg. 354, 1996). For example, Gujjaret al. have linked HRV and outcomes after acute severe stroke (“Heartrate variability and outcome in acute severe stroke,” NeurocriticalCare, vol. 1, pg. 347, 2004).

The CVS treatment was a 42° C. sawtooth wave applied to the left ear anda 17° C. sawtooth applied to the right ear. The treatment lasted for 10minutes. HRV data were recorded immediately after the end of thetreatment. HRV is a dimensionless measure. During the October 24^(th)test, average HRV dropped by 30% and on October 28^(th) by 27% (data notshown).

Discussion:

HRV is proposed as a marker of effective CVS induction and could thus beused as a tool for titrating CVS dosing. Pathological conditions (suchas cluster headaches discussed here) can lead to elevated HRV levels.Other pathological conditions, e.g. cardiac insufficiencies, are oftenassociated with abnormally low HRV values (for that individual).

Example 26 Treatment of Fibromyalgia

A subject (also female, age 50-55) was diagnosed with fibromyalgia 3years ago. Multiple allopathic and homeopathic interventions provided nosubstantive relief. The subject has co-morbid migraine headaches.

Methods and Results:

The subject underwent CVS treatment in the right ear, with a 17 degreeC. sawtooth waveform.

From September 13-19 the subject stopped CVS treatment due tosignificant pain and inability to function. On September 20 the subjectbegan treatments twice per day, sometimes using a 3^(rd) daily treatmentusing the CVS parameters listed above. She realized an improvement inboth migraine pain and pain from fibromyalgia. In the September 28-30timeframe thunderstorms seemed to trigger additional migraine pain, butthis abated over the following days until her pain level was barelynoticeable.

The subject commented upon starting twice-a-day treatments: “I'm writingto report excellent results using 2 treatments. Last night I tried 2consecutive treatments, and I felt great! Like I'd been to a spa and hada relaxing massage and soak in the hot tub.”

The subject reported on September 26^(th): “This weekend I was able towork with [husband] getting 14 new bushes in the yard and picking outnew paint at Lowe's to repaint the shutters on the house. I'm so veryhopeful and happy. Gardening is a shared passion for us, and the firsttwo years here, I wasn't able to even water the plants, so the ones leftare real survivors! I feel like you are giving me my life back, andgiving [husband] his wife back.”

When the subject's spouse was asked if the CVS device was truly helpfulhe responded: “Nothing in the last 3 years had helped before this.”

After October 6, the unit was retrieved. The subject has since returnedto baseline.

Example 27 Treatment of Peripheral Neuropathy

A female subject underwent spinal surgery and sustained damage to thespinal cord. Thereafter she has had intractable peripheral neuropathy(foot pain) over a roughly 4 month period that had not responded toanalgesics. The subject has obtained relief using CVS, with the extentand duration of relief depending on the device used and the waveformdetails.

Methods and Results:

The subject underwent CVS treatment with the following chronology:

1. Dual ear CVS unit: L-ear, sawtooth, 34 to 20° C.; R-ear, sawtooth, 34to 42° C., 10 min. therapy. The treatment made her very sleepy (deepsleep for 20 min) Within 30 minutes, she was pain free and stayed so for3 days, which was extraordinary for her.

2. Single (right) ear CVS unit, sawtooth, 34 to 17° C., 10 min therapy.She realized about a 50% reduction in pain level that lasted around 2hours.

3. Single (right) ear CVS unit, long (single rise) square wave, 34 to48° C., 10 min. She finds that the single ear, warm treatment is betterthan single ear, cold treatment. She must use the device several times aday to achieve pain relief.

4. Dual ear CVS unit, L-ear 17° C. square wave, R-ear 44° C. sawtooth,10 min. Deep sleep for 45 min (at 5 PM). Foot pain ceased.

Discussion: The subject received extended (multiple day) pain relieffrom one 10 min session using dual ear CVS. Single ear CVS, using asawtooth waveform (slower slew rate) and an early device (basically asingle cold/warm square wave), led to partial pain reduction for a timelimited to hours. Therefore, the dual ear CVS treatment was superior tosingle ear for pain reduction. This subject and another have stated thatthe mixed waveform, dual ear (e.g., example 4) results in moresignificant subjective sensations (deep relaxation/sleep for thissubject, increased nausea for the other). It is unclear with this singlecase if the mixed waveform treatment leads to increased pain reductionefficacy (both dual ear treatments were significant).

Example 28 Single Ear Treatment of Episodic Migraine

This Example evaluates the feasibility of using a portable CVS unit in ahome setting over a month or more. The hypothesis was that daily CVStreatment would reduce the overall pain level and frequency ofheadaches.

Methods and Results:

The subject is a 50-55 year old female with a history of 6-8 migraineheadache days per month (a month is taken as 28 days when reporting onmigraine frequency). The subject used a right-ear CVS device and asawtooth waveform that went from 34° C. to 17° C. with a period ofroughly 1.7 minutes. The duration of the treatment was 10 minutes persession (daily sessions, moving to every other day after about 2 weeksof treatment). The average slew rate for heating was 40° C./minute andthe average slew rate for cooling was 14° C./minute.

The subject experienced a decrease in pain over the first week oftherapy. (pain score data not shown). In the 40 days past the one weektransitionary period, the subject had only one migraine headache (again,to qualify as a migraine it must be at a pain level of 6 or more on ascale of zero to ten and last for 4 hours or more). The one headacheoccurred during unusual stress associated with a transatlantic trip anddisruption of work schedule upon her return. The subject also noted asubjective improvement in co-morbid depression over the treatmentperiod.

Example 29 Titration of CVS Therapy for Type II Diabetes

The intent of this report is to show experimental evidence of thecontrol of glucose levels by adjusting the frequency with which CVS isused in a subject with type II diabetes.

Methods and Results:

The subject is a 40-45 year old male diagnosed with type II diabeteswithin the last two years. As reported earlier, the subject has beenable to forego the use of medications to control serum glucose levels,using CVS therapy instead. Recently, the subject has started using dualear CVS, with a warm time-varying waveform applied to one ear and a coldtime-varying waveform applied to the other. The dual ear therapy reducedthe frequency with which the subject needed to use CVS in order tocontrol serum glucose levels (data not shown). Dual ear CVS was usedwith a 17° C. square wave for the right ear and a 42° C. sawtooth on theleft ear. Each point in the graph represents a daily measurement(consistent time during each day). The red lines show when CVS was used.As the glucose levels were tracked, they would tend to move up inbetween CVS treatments, thus signaling when another treatment should beapplied. This feedback method should be able to be extended to otherpatients, using their specific glucose levels to titrate frequency andintensity of CVS treatments. This subject remains off any othermedications to control glucose levels.

Discussion:

This is an update report to supplement accounts from this subjectalready included in the Examples above, and further shows that serumglucose is a useful metric for CVS titration.

Example 30 CVS Intensity for Different Waveforms

As the CVS treatment device has evolved, we have moved from single todual ear stimulation and have increased the slew rate to allow waveformsto be played out at a higher frequency. This report lists subjectivemetrics that can be used to assess the strength of CVS stimulation for agiven subject.

Methods and Results:

The subject is a 40-45 year old male using CVS therapy chronically fortype II diabetes and seasonal cluster headaches. He ranks the level ofintensity of the CVS experience as follows:

-   -   single ear:        -   daily treatments were required to control cluster headaches            and serum glucose levels        -   typical treatment is a cold sawtooth wave going between 34            and 17° C.    -   dual ear, same waveform shape, warm and cold:        -   only 1-3 treatments per week are needed to control cluster            headaches and serum glucose        -   typical waveform is a sawtooth going from 34 to 42-44° C. in            one ear and 34 to 17° C. in the other ear.        -   Not much subjective difference compared with single ear            during treatment            -   More pronounced dizziness upon standing            -   Nausea more persistent            -   Faster, more complete responses for increased pain level            -   Blurred vision for 3-5 minutes (possibly nystagmus)    -   dual ear, different waveform shape, warm and cold:        -   only 1-3 treatments per week are needed to control cluster            headaches and serum glucose        -   typical waveform is a sawtooth going from 34 to 42-44° C. in            one ear and a square wave in the other ear going from 34 to            17-20° C.        -   most potent of all types tried in terms of pain mitigation            and positive mood effects (side effects do not outweigh            additional benefits)            -   sleep inducing            -   nausea while in horizontal position            -   significant nausea and brief period of poor postural                control upon standing            -   persistent feeling of head fullness

Discussion:

The most significant metrics for CVS therapy for pain patients is itseffects on pain level and relative side effects. This report recountsobservations by one subject that can serve as a paradigm for how otherpatients can be assessed in the clinic. The right titration will involvean on-going assessment of effects on symptoms (e.g., pain) andminimization of unwanted, lasting side effects (for clarity, the sideeffects reported above are transient). There are tradeoffs that patientscan make between efficacy with more intense side effects balancedagainst less frequent need to treat.

The following parameters can be varied in a dual ear system:

-   -   1. temperature (magnitude and sign with respect to body        temperature)    -   2. waveform shape    -   3. frequency of waveform(s); if they are different frequencies,        they could be commensurate and beat frequencies could be        established.    -   4. relative phase of waveforms (e.g., in phase or some degree of        being out of phase if they have the same frequency)    -   5. variable frequency during the course of a treatment (each        side)

The CVS device can be programmed, in principal, to play out a differentcombination every day, thus frustrating any tendency of the VS of thepatient to adapt to a given therapeutic waveform. This is a principaladvantage of dual ear over single ear CVS.

Example 31 Treatment of Sleep Disorders/Insomnia with CVS

A common report from users of the CVS device is that they havebeneficial effects in terms of sleeping soundly. It is known (e.g.,Horii et al., J. Neurophysiol, 70, 1822, (1993)) that CVS does activatethe hypothalamus. The hypothalamus in turn controls the sleep/wake cyclein mammals.

Methods and Results:

The reports of the soporific effects of CVS with subjects is variableand subjective. Listing the claims by subjects in order of frequency:

1. a relaxed feeling right after the completion of a CVS treatment

2. report of having an exceptionally complete sleep cycle on the nightfollowing a CVS treatment

3. A very powerful soporific effect that resulted in the subject fallingasleep during a 10-20 minute CVS treatment and staying asleep for up toseveral hours.

Examples of Each of the Observations Listed Above:

1. A small pilot clinical trial was performed at a private headacheclinic on patients who were being treated for migraine headache. The CVSwaveform used was a sawtooth, right ear only, with the temperatureoscillating between 34 and 17° C. None of the subjects fell asleepduring the 10 minute CVS treatment, but commonly reported being relaxedin a way that was greater than what they would feel when lying down, ina similar position, for the same amount of time.

2. A male, age 50-55 acting as a normal test subject used single ear(right) CVS, sawtooth waveform oscillating between 34 and 17° C. Hereported pleasant drowsiness after the 10 minute therapy session andthen reported that he′d slept exceptionally soundly that night.

3. A subject using CVS for foot pain (see previous Example on thissubject) used a dual ear CVS device: L-ear, sawtooth, 34 to 20° C.;R-ear, sawtooth, 34 to 42° C., 10 min. therapy. The treatment made hervery sleepy (deep sleep for 20 min). Then again: dual ear, L-ear 17° C.square wave, R-ear 44° C. sawtooth, 10 min Deep sleep for 45 min (at 5PM) and had to be awakened.

In all cases, subjects reported restful sleep versus “forced” sleep andthey reported no ill side effects.

Example 32 Single Ear CVS Treatment of Pediatric Epilepsy

The intent with this study was to evaluate using the Gen 2.0 CVS unit(left ear only, same earpiece but different (less powerful) TEC(thermoelectric cooler or Peltier cooler) than will be used in Gen 3device) in a single session to observe any effects on spike activity inepileptic patients as monitored by EEG.

Methods and Results:

The subjects were treated with a sawtooth waveform that went from 34° C.to 17° C. (left ear only). Note that the actual temperature profile wasnot the same for all patients. For patient 3, the average slew rate onheating was around 14-15° C./min and the cooling rate dropped from about5.8° C./min to 4.5° C./min (not shown). It can be seen that more timewas required to in the second “dip” to get to 17° C. This is due toinsufficient power in the Gen 2.0 CVS device.

For patient 4, the inadequate power of the unit is even more apparent.The average heating slew rate was about the same as with patient 3, butthe cooling rate started at 4.2° C./min and dropped to 3.6/min (notshown). The device failed to reach the 17° C. target temperature.

The spike rate was measured by continuous EEG before CVS treatment andafter CVS treatment (data not shown). The decrease in spike rate lastedfrom 1-2 hours for each of the four patients. The reduction in spikingranges from 21-32%.

Discussion:

despite the underperformance of the Gen 2.0 model, primarily caused byan older, less powerful TEC and the lack of a cooling fan on the heatsink, demonstrable effects were seen in all 4 patients in terms of areduction in spike activity that persisted past the end of the CVStreatment session. At this time, we don't have the ability to try a moreadvanced device (e.g., Gen 2.5) with these patients. A logical coursewould be to treat the patients longitudinally to see if the effects ofCVS could be made more lasting. Despite the challenge of performing CVSon this population (age range from 6-10 years old), it was accomplishedand there were no side effects of the treatment.

The foregoing is illustrative of the present invention and is not to beconstrued as limiting thereof. Although a few exemplary embodiments ofthis invention have been described, those skilled in the art willreadily appreciate that many modifications are possible in the exemplaryembodiments without materially departing from the novel teachings andadvantages of this invention. Accordingly, all such modifications areintended to be included within the scope of this invention as defined inthe claims. Therefore, it is to be understood that the foregoing isillustrative of the present invention and is not to be construed aslimited to the specific embodiments disclosed, and that modifications tothe disclosed embodiments, as well as other embodiments, are intended tobe included within the scope of the appended claims. The invention isdefined by the following claims, with equivalents of the claims to beincluded therein.

That which is claimed is:
 1. An in-ear stimulation device foradministering caloric stimulation to the ear canal of a subject,comprising: (a) first and second earpieces configured to be insertableinto the ear canals of the subject; (b) at least first and secondthermoelectric devices thermally coupled to respective ones of the firstand second earpieces; (c) a first heat sink thermally coupled to thefirst thermoelectric device opposite the first earpiece and a secondheat sink thermally coupled to the second thermoelectric device oppositethe second earpiece; and (d) a controller comprising a waveformgenerator in communication with the first and second thermoelectricdevices, the waveform generator configured to generate a first controlsignal to control a first caloric output to the first thermoelectricdevice and a second control signal to control a second caloric output tothe second thermoelectric device.